bims-aporos Biomed News
on Apoptosis and reactive oxygen species
Issue of 2019‒07‒21
fifty-four papers selected by
Gavin McStay
Staffordshire University
  1. Protective Effects of Zinc on 2.45 GHz Electromagnetic Radiation-Induced Oxidative Stress and Apoptosis in HEK293 Cells.
  2. Cytotoxic effects, inflammatory response and apoptosis induction of cyclophosphamide in the peripheral blood leukocyte of blunt snout bream (Megalobrama amblycephala).
  3. Therapeutic effect of yttrium oxide nanoparticles for the treatment of fulminant hepatic failure.
  4. Ethyl acetate extracts of Nepenthes ventricosa x sibuyanensis leaves cause growth inhibition against oral cancer cells via oxidative stress.
  5. Nicorandil prevents doxorubicin-induced human umbilical vein endothelial cell apoptosis.
  6. Cinobufagin induced cell apoptosis and protective autophagy through the ROS/MAPK signaling pathway.
  7. Andrographolide sensitizes Hep-2 human laryngeal cancer cells to carboplatin-induced apoptosis by increasing reactive oxygen species levels.
  8. Troxerutin exerts neuroprotection against lipopolysaccharide (LPS) induced oxidative stress and neuroinflammation through targeting SIRT1/SIRT3 signaling pathway.
  9. TIGAR impedes compression-induced intervertebral disc degeneration by suppressing nucleus pulposus cell apoptosis and autophagy.
  10. Two novel 1,4‑naphthoquinone derivatives induce human gastric cancer cell apoptosis and cell cycle arrest by regulating reactive oxygen species‑mediated MAPK/Akt/STAT3 signaling pathways.
  11. P16INK4a played a critical role in exacerbating acute tubular necrosis in acute kidney injury.
  12. Zinc Deficiency Promotes Testicular Cell Apoptosis in Mice.
  13. Examining the involvement of Slx5 in the apoptotic response to chronic activation of the spindle assembly checkpoint.
  14. MitoQ ameliorates testicular damage induced by gamma irradiation in rats: Modulation of mitochondrial apoptosis and steroidogenesis.
  15. Bavachinin exhibits antitumor activity against non‑small cell lung cancer by targeting PPARγ.
  16. Apigenin Protects Against Renal Tubular Epithelial Cell Injury and Oxidative Stress by High Glucose via Regulation of NF-E2-Related Factor 2 (Nrf2) Pathway.
  17. Recombinant α-Klotho Protein Alleviated Acute Cardiorenal Injury in a Mouse Model of Lipopolysaccharide-Induced Septic Cardiorenal Syndrome Type 5.
  18. Curcumin ameliorates atrophy of seminal vesicle via reduction of oxidative stress in castrated mice.
  19. Targeting mitochondria through the use of mitocans as emerging anticancer agents.
  20. Protective effects of hepatocyte growth factor gene overexpression against hydrogen peroxide-induced apoptosis in mesenchymal stem cells.
  21. Testicular toxicity of gentamicin in adult rats: Ameliorative effect of lycopene.
  22. Paeonol protects mitochondrial injury and prevents pulmonary vascular remodeling in hypoxia.
  23. Typhaneoside prevents acute myeloid leukemia (AML) through suppressing proliferation and inducing ferroptosis associated with autophagy.
  24. C-Phycocyanin Ameliorates Mitochondrial Fission and Fusion Dynamics in Ischemic Cardiomyocyte Damage.
  25. Retinal Pigment Epithelium Cell Death Is Associated With NLRP3 Inflammasome Activation by All-trans Retinal.
  26. Propofol directly induces caspase-1-dependent macrophage pyroptosis through the NLRP3-ASC inflammasome.
  27. Green synthesis of gold nanoparticles using a Cordyceps militaris extract and their antiproliferative effect in liver cancer cells (HepG2).
  28. Effect of crocin on biochemical parameters, oxidative/antioxidative profiles, sperm characteristics and testicular histopathology in streptozotocin-induced diabetic rats.
  29. Novel peptide myristoly-CM4 induces selective cytotoxicity in leukemia K562/MDR and Jurkat cells by necrosis and/or apoptosis pathway.
  30. Hepatoprotective effects of ethyl pyruvate against carbon tetrachloride-induced oxidative stress, biochemical and histological alterations in rats.
  31. β-carotene improves oocyte development and maturation under oxidative stress in vitro.
  32. WX20120108, a novel IAP antagonist, induces tumor cell autophagy via activating ROS-FOXO pathway.
  33. [Effects of short-chain acyl-CoA dehydrogenase on human umbilical vein endothelial cell apoptosis].
  34. Administration of troxerutin improves testicular function and structure in type-1 diabetic adult rats by reduction of apoptosis.
  35. Chlorpyrifos induced oxidative stress to promote apoptosis and autophagy through the regulation of miR-19a-AMPK axis in common carp.
  36. Tris(8-Hydroxyquinoline)iron induces apoptotic cell death via oxidative stress and by activating death receptor signaling pathway in human head and neck carcinoma cells.
  37. Syndecan-4 involves in the pathogenesis of rheumatoid arthritis by regulating the inflammatory response and apoptosis of fibroblast-like synoviocytes.
  38. Drug delivery micelles with efficient near-infrared photosensitizer for combined image-guided photodynamic therapy and chemotherapy of drug-resistant cancer.
  39. A Biomimetic Superoxide Disproportionation Catalyst for Anti-Aging Lithium-Oxygen Batteries.
  40. Ginsenoside Rg5 induces G2/M phase arrest, apoptosis and autophagy via regulating ROS-mediated MAPK pathways against human gastric cancer.
  41. Protein kinase A activation by β‑Lapachone is associated with apoptotic cell death in NQO1‑overexpressing breast cancer cells.
  42. The protective effects of lycopus lucidus turcz in diabetic retinopathy and its possible mechanisms.
  43. Extracellular Histones Induced Eryptotic Death in Human Erythrocytes.
  44. Pharmacological preconditioning with phosphodiestrase inhibitor: an answer to stem cell survival against ischemic injury through JAK/STAT signaling.
  45. Effect of a Prolonged Dietary Iron Intake on the Gene Expression and Activity of the Testicular Antioxidant Defense System in Rats.
  46. Cytotoxic and Antitumor Activity of Lactaptin in Combination with Autophagy Inducers and Inhibitors.
  47. The link between advanced glycation end products and apoptosis in delayed wound healing.
  48. MiR-320a was highly expressed in postmenopausal osteoporosis and acts as a negative regulator in MC3T3E1 cells by reducing MAP9 and inhibiting PI3K/AKT signaling pathway.
  49. Palbociclib improves cardiac dysfunction in diabetic cardiomyopathy by regulating Rb phosphorylation.
  50. The role of DJ-1 in human primary alveolar type II cell injury induced by e-cigarette aerosol.
  51. Elafibranor Inhibits Chronic Kidney Disease Progression in NASH Mice.
  52. Preparation, structural characterization and bioactivity of 4-O-Methylglucuronoxylan from Artemisia sphaerocephala Krasch.
  53. Endothelial Mitochondrial Dysfunction in Cerebral Amyloid Angiopathy and Alzheimer's Disease.
  54. HNF1β protects endometriotic cells against apoptotic cell death by upregulating the expression of anti-apoptotic genes.
  1. Biol Trace Elem Res. 2019 Jul 17.
    Protective Effects of Zinc on 2.45 GHz Electromagnetic Radiation-Induced Oxidative Stress and Apoptosis in HEK293 Cells.
    Nural Pastacı Özsobacı, Dilek Düzgün Ergün, Matem Tunçdemir, Derviş Özçelik.
      Several epidemiological studies have shown that exposure to electromagnetic radiation (EMR) can be harmful to human health. The purpose of this study was to examine oxidative parameters and apoptosis induced by EMR in human kidney embryonic cells (HEK293) and to investigate whether zinc (Zn) has protective effect on EMR-induced apoptosis in HEK293 cells. For our experiment, HEK293 cells were divided into four main groups, control, EMR, 50 μM Zn + EMR, and 100 μM Zn + EMR. HEK293 cells of EMR groups were exposed to 2.45 GHz EMR for 1 h. In Zn groups, HEK293 cells were incubated with different concentrations of Zn for 48 h before EMR exposure. Oxidative stress parameters were determined by spectrophotometric method; bcl-2 and caspase-3 were assessed immunohistochemically and TUNEL method was performed for apoptotic activity. EMR group had higher malondialdehyde (MDA) level and lower superoxide dismutase (SOD) activity compared with control group. In Zn-applied groups, MDA was decreased and SOD activity was increased compared with EMR group. The number of the apoptotic cells and caspase-3 immunopositive cells at EMR group was increased significantly compared with the control group, whereas bcl-2 was decreased. Besides, Zn-treated groups showed a significant reduction in the number of apoptotic cells and caspase-3 from that of EMR group, whereas there was an increase in bcl-2 immunopositivity. Our findings show that EMR caused oxidative stress and apoptotic activation in HEK293 cells. Zn seems to have protective effects on the EMR by increasing SOD activity and bcl-2 immunopositivity, decreasing lipid peroxidation and caspas-3 immunopositivity.
    Keywords:  Apoptosis; Electromagnetic radiation; HEK293; Oxidative stress; Zinc
    DOI:  https://doi.org/10.1007/s12011-019-01811-6
  2. Fish Shellfish Immunol. 2019 Jul 11. pii: S1050-4648(19)30723-5. [Epub ahead of print]
    Cytotoxic effects, inflammatory response and apoptosis induction of cyclophosphamide in the peripheral blood leukocyte of blunt snout bream (Megalobrama amblycephala).
    Bo Liu, Zhenfei Yang, Liu Bo, Zhenxin Zhao, Qunlan Zhou, Cunxin Sun.
      The present study was aimed to evaluate the effects of the cyclophosphamide (CY) exposure (Control, 0.032, 0.32, 1.0, 1.6 and 3.2 mg/ml) on the damage in the peripheral blood leukocytes of blunt snout bream for 24 h, which including cell viability, apoptosis, lactate dehydrogenase (LDH) release, mitochondrial membrane potential (Δѱm), ROS, antioxidant enzyme activity and the relative mRNA levels of apoptosis. Results showed that cell viability and Δѱm effects of CY were greatly reduced, and occurred in a dose-dependent manner. CY exposure (0.32-3.2 mg/ml) significantly increased the LDH release and induced apoptosis accompanied by ΔΨm disruption and ROS generation compared to the control. The cellular ROS was significantly increased with increase of CY level from 0.032 mg/ml to 1 mg/ml and the plateau occurred at 0.32 mg/ml. Additionally CY exposure led to oxidative stress as evidenced by significantly the decrease of SOD and CAT and increase of MDA concentration after treating cells with 3.2 mg/ml of CY. Besides, the relative mRNA levels of caspase-3 in the dose of 0.032, 0.32 mg/ml CY, caspase-9 and interleukins-1β (IL-1β) in the dose of 0.32 mg/ml CY, tumor necrosis factor-alpha (TNF-α) in the dose of 0.032 mg/ml CY significantly higher than that of the control. In conclusion, 0.32-3.2 mg/ml CY could lead to cytotoxic effect, inflammatory response and induce the apoptosis of the peripheral blood leukocyte of Megalobrama amblycephala.
    Keywords:  Apoptosis; Cyclophosphamide; Cytotoxicity; M.amblycephala; Peripheral blood leukocyte
    DOI:  https://doi.org/10.1016/j.fsi.2019.07.014
  3. Nanomedicine (Lond). 2019 Jul 18.
    Therapeutic effect of yttrium oxide nanoparticles for the treatment of fulminant hepatic failure.
    Xiang Song, Pan Shang, Zhenwei Sun, Mingzi Lu, Guoxing You, Shaoduo Yan, Gan Chen, Hong Zhou.
      Aim: To explore the potential therapeutic effect of yttrium oxide nanoparticles (Y2O3 NPs) on fulminant hepatic failure. Materials & methods: RAW264.7 cells and a lipopolysaccharide/D-galactosamine-induced hepatic failure murine model were used to assess the effects of Y2O3 NPs. Results: Y2O3 NPs exhibited anti-inflammatory activity by scavenging cellular reactive oxygen species and dampening reactive oxygen species-mediated NF-κB activation in vitro. A single intraperitoneal administration of Y2O3 NPs (30 mg/kg) enhanced hepatic antioxidant status and reduced oxidative stress and inflammatory response in lipopolysaccharide/galactosamine-induced mice. Y2O3 NPs also attenuated hepatic NF-κB activation, cell apoptosis and liver injury. Conclusion: Y2O3 NP administration could be used as a novel therapeutic strategy for treating fulminant hepatic failure and oxidative stress-related diseases.
    Keywords:  D-galactosamine; NF-κB activation; cerium oxide nanoparticles; fulminant hepatic failure; inflammation; lipopolysaccharide; reactive oxygen species; yttrium oxide nanoparticles
    DOI:  https://doi.org/10.2217/nnm-2019-0154
  4. Onco Targets Ther. 2019 ;12 5227-5239
    Ethyl acetate extracts of Nepenthes ventricosa x sibuyanensis leaves cause growth inhibition against oral cancer cells via oxidative stress.
    Jen-Yang Tang, Tzu-Jung Yu, Li-Ching Lin, Sheng-Yao Peng, Chun-Lin Wang, Fu Ou-Yang, Yuan-Bin Cheng, Hsueh-Wei Chang.
      Introduction: The genus Nepenthes of the pitcher plants contains several natural and hybrid species that are commonly used in herbal medicine in several countries, but its possible use in cancer applications remains unknown as yet. Methods: In this study, we investigated the antioral cancer properties using ethyl acetate extracts of the Nepenthes hybrid (Nepenthes ventricosa x sibuyanensis), namely EANS. The bioactivity was detected by a MTS-based cell proliferation assay and flow cytometric or Western blot analysis for apoptosis, oxidative stress, and DNA damage. Results: Treatment for 24 hrs of EANS inhibited all three types of oral cancer cells that were tested (Ca9-22, CAL 27, and SCC9), with just a small difference to normal oral cells (HGF-1). This antiproliferation was inhibited by pretreatments with the reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC), and the apoptosis inhibitor (Z-VAD). EANS treatment increased the subG1 population and it also dose- and time-dependently induced annexin V- and pancaspase-detected apoptosis as well as cleaved caspases 3 and 9 overexpressions in the oral cancer cells (Ca9-22). After EANS treatment of Ca9-22 cells, intracellular ROS and mitochondrial superoxide (MitoSOX) were overexpressed and mitochondrial membrane potential (MMP) was disrupted. Moreover, DNA damages such as γH2AX and 8-oxo-2'-deoxyguanosine (8-oxodG) were increased after EANS treatment to Ca9-22 cells. The EANS-induced effects (namely, oxidative stress, apoptosis, and DNA damage) were suppressed by ROS scavenger. Conclusion: Our findings demonstrated that EANS inhibits ROS-mediated proliferation against oral cancer cells.
    Keywords:  DNA damage; Nepenthes; apoptosis; oral cancer; oxidative stress
    DOI:  https://doi.org/10.2147/OTT.S190460
  5. Eur J Pharmacol. 2019 Jul 15. pii: S0014-2999(19)30494-7. [Epub ahead of print] 172542
    Nicorandil prevents doxorubicin-induced human umbilical vein endothelial cell apoptosis.
    Chun-Chao Chen, Hong-Jye Hong, Wen-Rui Hao, Tzu-Hurng Cheng, Ju-Chi Liu, Li-Chin Sung.
      Nicorandil is an adenosine triphosphate-sensitive potassium channel opener with additional antioxidant properties. Doxorubicin (DOX) is an anticancer drug that exerts oxidation-mediated adverse cardiovascular effects. This study examined the effects of nicorandil on DOX-induced cytotoxicity in human umbilical vein endothelial cells (HUVECs) and underlying intracellular signaling mechanisms. Cultured HUVECs were pretreated with nicorandil (0.1, 0.3, 1, 3, and 10 μM) for 12 h and then treated with DOX (1 μM) for 24 h. Cell viability and cytotoxicity were measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase assays, respectively. Cell apoptosis was examined using a caspase-3 activity assay, and DNA fragmentation was detected through TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) staining. Western blot analysis was conducted to determine the related protein expression. DOX markedly increased reactive oxygen species production, p53 expression, caspase-3 activity, cleaved caspase-3 levels, and TUNEL-positive cell numbers but reduced Bcl-2 expression and intracellular antioxidant enzyme levels; these effects were effectively antagonized through nicorandil (3 μM, 12 h) pretreatment, which resulted in HUVECs being protected from DOX-induced apoptosis. Activating transcription factor 3 (ATF3), a stress-induced transcription factor, was induced by nicorandil (3 μM). Furthermore, nicorandil (3 μM) enhanced nuclear factor erythroid 2-related factor 2 (Nrf2) translocation and heme oxygenase-1 (HO-1) expression. ATF3 short interfering RNA significantly attenuated nicorandil-mediated Nrf2 translocation, HO-1 expression, and inhibitory effects on DOX-stimulated reactive oxygen species production and cell apoptosis. In summary, nicorandil may protect HUVECs from DOX-induced apoptosis, in part through ATF3-mediated Nrf2/HO-1 signaling pathways, which potentially protect the vessels from severe DOX toxicity.
    Keywords:  Apoptosis; Doxorubicin; Endothelial cells; Nicorandil; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.ejphar.2019.172542
  6. Life Sci. 2019 Jul 10. pii: S0024-3205(19)30568-5. [Epub ahead of print] 116642
    Cinobufagin induced cell apoptosis and protective autophagy through the ROS/MAPK signaling pathway.
    Kaili Wang, Danxia Chu, Jie Wu, Mengling Zhao, Miaomiao Zhang, Bijun Li, Wenjun Du, Jianmin Du, Ruixia Guo.
      PURPOSE: Cinobufagin(CB), an cardiotonic steroid isolated from the skin and parotid venom glands of the toad Bufo bufo gargarizans Cantor, has reported to have a significant anti-cancer effect on various cancers. However, the effect of CB on ovarian cancers was none reported. Herein, the present study aimed to investigate the therapeutic effect of cinobufagin on the ovarian cancer cells and elucidate the underlying mechanism.METHODS: Cell viability in our work was assessed via MTT. Cell apoptosis was detected by flow cytometry analysis and Hoechst 33258. Autophagy was defined by confocal microscopy after infected with mRFP-GFP-LC3 dual fluorescence adenovirus. Reactive oxygen species (ROS) was investigated by flow cytometry. The level of marker proteins involved in autophagy, apoptosis and ROS/MAPK signaling pathway were determined by western blot.
    RESULTS: Cinobufagin significantly reduced the viability and induced apoptotic cell death of human ovarian cancer cell lines SKOV-3 and A2780. MRFP-GFP-LC3 infection elaborated that cinobufagin could promote cell autophagy. Moreover, autophagy inhibitor 3-methyladenine (3-MA) markedly enhanced the cinobufagin-induced apoptosis. In addition, treatment with cinobufagin could dramatically increase the expression of ROS and then activate the phosphorylation of MAPK family proteins, including ERK 1/2, JNK and p38. What's more, the reaction of apoptosis and autophagy induced by cinobufagin treatment could be reversed by p38 inhibitor SB203580 and JNK inhibitor SP600125 as well as ROS exclusive inhibitor antioxidant N-acetyl cysteine (NAC).
    CONCLUSIONS: Our findings provide clues concluding that cinobufagin could induce cell apoptosis and protective autophagy through the ROS/MAPK signaling pathway in human ovarian cancer cells.
    Keywords:  Autophagy; Cell apoptosis; Cinobufagin; Ovarian cancer; ROS/MAPK signaling pathway
    DOI:  https://doi.org/10.1016/j.lfs.2019.116642
  7. Anticancer Drugs. 2019 Aug;30(7): e0774
    Andrographolide sensitizes Hep-2 human laryngeal cancer cells to carboplatin-induced apoptosis by increasing reactive oxygen species levels.
    Wenjing Mao, Peijie He, Weicheng Wang, Xiufa Wu, Chunsheng Wei.
      Andrographolide is a natural diterpenoid from Andrographis paniculata that has been proposed as an anticancer agent as well as a chemosensitizer for use in combination with anticancer drugs. Carboplatin is the first-line chemotherapeutic agent for advanced laryngeal carcinoma. However, the clinical efficacy of carboplatin is limited by drug resistance and side effects. The aim of this study was to investigate whether andrographolide has a synergistic antitumor effect with carboplatin on human laryngeal cancer cells. Hep-2 cells were exposed to andrographolide with or without carboplatin. The effects of indicated therapies were examined using the Cell Counting Kit-8 assay, the colony-forming assay, the Hoechst 33342/PI double staining, and flow cytometry analysis. The molecular mechanism was assessed by reactive oxygen species (ROS) detection and western blot. At the sublethal concentration, andrographolide increased carboplatin sensitivity of Hep-2 cells by increasing carboplatin-induced apoptosis and inhibiting cell viability. Moreover, we found that andrographolide sensitized carboplatin mainly through the induction of ROS generation and apoptotic signaling. Taken together, these results indicate that andrographolide, along with carboplatin, synergistically inhibited cell proliferation and induced mitochondrial apoptosis of Hep-2 cells by increasing the intracellular ROS, regulating the mitogen-activated protein kinase and phosphatidylinositol 3-kinase (PI3K/AKT) pathways, altering the BCL2/BAX ratio, and ultimately activating the cleavage of Caspase-3 and PARP. These results suggest that andrographolide sensitizes human laryngeal cancer cells to carboplatin-induced apoptosis by increasing ROS levels.
    DOI:  https://doi.org/10.1097/CAD.0000000000000774
  8. Metab Brain Dis. 2019 Jul 16.
    Troxerutin exerts neuroprotection against lipopolysaccharide (LPS) induced oxidative stress and neuroinflammation through targeting SIRT1/SIRT3 signaling pathway.
    Nida Jamali-Raeufy, Sedighe Kardgar, Tourandokht Baluchnejadmojarad, Mehrdad Roghani, Mina Goudarzi.
      This study was conducted to clarify the potential mechanisms of Troxerutin neuroprotection against Lipopolysaccharide (LPS) induced oxidative stress and neuroinflammation through targeting the SIRT1/SIRT3 signaling pathway. To establish a model, a single dose of LPS (500μg/kg body weight) was injected to male Wistar rats intraperitoneally. Troxerutin (100 mg/kg body weight) was injected intraperitoneally for 5 days after induction of the model. Cognitive and behavioral evaluations were performed using Y-maze, single-trial passive avoidance, and novel object recognition tests. The expression of inflammatory mediators, SIRT1/SIRT3, and P53 was measured using the ELISA assay. Likewise, the expression levels of SIRT1/SIRT3 and NF-κB were determined using Western blot assay. Brain acetyl-cholinesterase activity was determined by utilizing the method of Ellman. Reactive oxygen species (ROS) was detected using Fluorescent probe 2, 7-dichlorofluorescein diacetate (DCFH-DA). Furthermore, malondialdehyde (MDA) levels were determined. A single intraperitoneal injection of LPS was led to ROS production, acute neuroinflammation, apoptotic cell death, and inactivation of the SIRT1/SIRT3 signaling pathway. Likewise, ELISA assay demonstrated that post-treatment with Troxerutin considerably suppressed LPS-induced acute neuroinflammation, oxidative stress, apoptosis and subsequently memory impairments by targeting SIRT1/SIRT3 signaling pathway. Western blot assay confirmed ELISA results about SIRT1/SIRT3 and NF-κB proteins. These results suggest that Troxerutin can be a suitable candidate to treat neuroinflammation caused by neurodegenerative disorders.
    Keywords:  Lipopolysaccharide; Neuroinflammation; Oxidative stress; SIRT1; SIRT3; Troxerutin
    DOI:  https://doi.org/10.1007/s11011-019-00454-9
  9. J Cell Physiol. 2019 Jul 17.
    TIGAR impedes compression-induced intervertebral disc degeneration by suppressing nucleus pulposus cell apoptosis and autophagy.
    Zhiliang Li, Zengwu Shao, Songfeng Chen, Donghua Huang, Yizhong Peng, Sheng Chen, Kaige Ma.
      To investigate whether TP53-induced glycolysis and apoptosis regulator (TIGAR) participates in compression-induced intervertebral disc (IVD) degeneration, and to determine the regulatory effect of TIGAR on nucleus pulposus (NP) cell autophagy and apoptosis following compression-induced injuries. IVD tissues were collected from human patients undergoing surgery (n = 20) and skeletally mature Sprague-Dawley rats (n = 15). Initially, the effect of compression on the expression of TIGAR was evaluated with in vivo and in vitro models. In addition, TIGAR was silenced to investigate the regulatory effect of TIGAR on compression-induced intracellular reactive oxygen species (ROS) levels, autophagy, and apoptosis in rat NP cells. Furthermore, the P53 inhibitor pifithrin-α (PFTα) and SP1 inhibitor mithramycin A were employed to detect expression level changes of TIGAR and autophagy-associated target molecules. TIGAR expression of NP cells increased gradually in human degenerative IVDs and in rat NP cells under compression both in vivo and in vitro. TIGAR knockdown enhanced compression-induced intracellular ROS generation and the NADPH/NADP+ and GSH/GSSG ratios. Moreover, TIGAR knockdown amplified the compression-induced caspase-3 activation and the apoptosis rate of rat NP cells. Likewise, knockdown of TIGAR significantly accelerated LC3B expression and autophagosome formation in rat NP cells during compression-induced injuries. The results also established that mithramycin A could inhibit TIGAR expression and autophagy levels in NP cells under compression conditions, while PFTα had no similar effect. Our data demonstrated that TIGAR acted as an important endogenous negative regulator of ROS levels, which might inhibit compression-induced apoptosis and autophagy through SP1-dependent mechanisms.
    Keywords:  TIGAR; apoptosis; autophagy; compression; intervertebral disc degeneration; reactive oxygen species
    DOI:  https://doi.org/10.1002/jcp.29097
  10. Mol Med Rep. 2019 Jul 15.
    Two novel 1,4‑naphthoquinone derivatives induce human gastric cancer cell apoptosis and cell cycle arrest by regulating reactive oxygen species‑mediated MAPK/Akt/STAT3 signaling pathways.
    Hao Wang, Ying-Hua Luo, Gui-Nan Shen, Xian-Ji Piao, Wan-Ting Xu, Yi Zhang, Jia-Ru Wang, Yu-Chao Feng, Jin-Qian Li, Yu Zhang, Tong Zhang, Shi-Nong Wang, Hui Xue, Hong-Xing Wang, Chang-Yuan Wang, Cheng-Hao Jin.
      1,4‑Naphthoquinone derivatives have superior anticancer effects, but their use has been severely limited in clinical practice due to adverse side effects. To reduce the side effects and extend the anticancer effects of 1,4‑naphthoquinone derivatives, 2‑(butane‑1‑sulfinyl)‑1,4‑naphthoquinone (BQ) and 2‑(octane‑1‑sulfinyl)‑1,4‑naphthoquinone (OQ) were synthesized, and their anticancer activities were investigated. The anti‑proliferation effects, determined by MTT assays, showed that BQ and OQ significantly inhibited the viability of gastric cancer cells and had no significant cytotoxic effect on normal cell lines. The apoptotic effect was determined by flow cytometry, and the results showed that BQ and OQ induced cell apoptosis by regulating the mitochondrial pathway and cell cycle arrest at the G2/M phase via inhibition of the Akt signaling pathway in AGS cells. Furthermore, BQ and OQ significantly increased the levels of reactive oxygen species (ROS) and this effect was blocked by the ROS scavenger NAC in AGS cells. BQ and OQ induced apoptosis by upregulating the protein expression of p38 and JNK and downregulating the levels of ERK and STAT3. Furthermore, expression levels of these proteins were also blocked after NAC treatment. These results demonstrated that BQ and OQ induced apoptosis and cell cycle arrest at the G2/M phase in AGS cells by stimulating ROS generation, which caused subsequent activation of MAPK, Akt and STAT3 signaling pathways. Thus, BQ and OQ may serve as potential therapeutic agents for the treatment of human gastric cancer.
    DOI:  https://doi.org/10.3892/mmr.2019.10500
  11. Am J Transl Res. 2019 ;11(6): 3850-3861
    P16INK4a played a critical role in exacerbating acute tubular necrosis in acute kidney injury.
    Xin Gu, Cheng-Yi Peng, Shi-Yu Lin, Zi-Yue Qin, Jia-Long Liang, Hong-Jie Chen, Chen-Xing Hou, Rong Wang, Ying-Qiang Du, Jian-Liang Jin, Zhi-Jian Yang.
      Acute kidney injury (AKI) is a common clinical syndrome with high morbidity and mortality, which is mostly caused by acute tubular necrosis (ATN). AKI is associated with many factors, including cell senescence, inflammatory infiltration, apoptosis and excessive accumulation of reactive oxygen species (ROS). P16INK4a (hereafter termed p16) inhibits cell cycle, and the absence of p16 can significantly slow the progression of cell senescence. We found that the expression of p16 was significantly increased after ATN. To determine whether p16 could exacerbate ATN degree and whether p16 deletion had protective effects against the ATN and renal dysfunction in AKI progression, glycerol-rhabdomyolysis-induced ATN was performed in eight-week-old p16 knockout and wild-type (WT) littermates. Their ATN phenotypes were analyzed; the levels of serum creatinine and serum urea nitrogen were detected; inflammation, cell apoptosis, ROS level and ROS signaling pathway molecules were examined using histopathological and molecular techniques. We found that compared to WT mice, p16 deletion has protective effects against the ATN phenotype and renal dysfunction in AKI progression through ameliorating inflammatory infiltration and proinflammatory factor expression by inhibiting NF-κB proinflammatory pathway, decreasing cell apoptosis by balancing the expressions between pro-apoptotic and anti-apoptotic molecules, and reducing ROS levels and downregulating ROS signaling pathway molecules including AIF, PGAM5 and KEAP1. Thus, p16 deletion or inhibition and p16 positive cell clearance would be a novel strategy for preventing ATN in AKI progression.
    Keywords:  NF-κB; acute kidney injury; acute tubular necrosis; p16INK4a; reactive oxygen species; renal cell apoptosis
  12. Biol Trace Elem Res. 2019 Jul 16.
    Zinc Deficiency Promotes Testicular Cell Apoptosis in Mice.
    Yu Chen, Jing Yang, Ying Wang, Mei Yang, Mengyao Guo.
      Zinc (Zn) plays an important role in spermatogenesis, and carbon tetrachloride (CCl4) induces testicular oxidative damage and cell death. The objective of the present study was to define the effects of Zn deficiency in combination with CCl4 treatment on testicular apoptosis and the associated mechanisms. Mice were fed the following diets with three different Zn levels for 6 weeks: normal zinc (ZN) diet (30 mg Zn/kg), zinc-deficient (ZD) diet (2 mg Zn/kg), and adequate zinc (ZA) diet (100 mg Zn/kg). Beginning in the third week, CCl4 was intraperitoneally injected into half of the mice in each diet group six times over 3 weeks. We found that Zn was distributed in various tissues and organs in normal mice and that the zinc content in the testis of normal mice was high. The Zn-deficient diet reduced the zinc concentration in the testis tissue, and the testicular/body weight ratio significantly decreased. Moreover, the TUNEL results proved that CCl4 stimulation of mice fed with a zinc-deficient diet caused marked apoptosis of testicular cells. Furthermore, the ROS levels in the testes obviously increased after Zn-deficient mice were stimulated with CCl4, whereas reduced glutathione (GSH) and glutathione peroxidase (GSH-Px) showed reduced activities. In addition, proteins associated with the apoptosis signaling pathway were detected with ELISA kits. P-p53, cleaved caspase-3, cleaved PRAP, p-Bad, p-JNK, p-ERK, and p-NF-κB p65 increased by varying degrees under zinc deficiency or CCl4 stimulation. All the data indicated that Zn deficiency significantly enhanced the harm to the testis induced by oxidative stress and damage, while CCl4 stimulation exacerbated the oxidative damage in testicular cells, leading to apoptosis through the activation of p53, MAPK, and NF-κB.
    Keywords:  Apoptosis; CCl4; Oxidative stress; Testis; Zinc deficiency
    DOI:  https://doi.org/10.1007/s12011-019-01821-4
  13. Turk J Biol. 2019 ;43(3): 189-197
    Examining the involvement of Slx5 in the apoptotic response to chronic activation of the spindle assembly checkpoint.
    Pınar Buket Atalay, Elif Ergin Çavuşoğlu, Öykü Aşci, Duygu Aygüneş.
      Microtubule-targeting agents represent one of the most successful groups of anticancer drugs used in cancer therapy today. These drugs induce a prolonged mitotic arrest through chronic spindle assembly checkpoint (SAC) activation. Apoptosis, an outcome of the prolonged mitotic arrest, is the main mechanism by which these anticancer drugs kill cancer cells. However, not much is known about the mechanism that directs chronic SAC activation to apoptosis among other possible outcomes. The aim of this study is to investigate whether Slx5, a sumo-targeted ubiquitin E3 ligase, is involved in directing chronic SAC activation to apoptosis. We show that chronic SAC activation triggered by a 10-h nocodazole incubation leads to a prolonged mitotic arrest in the slx5Δ strain similar to wild type (WT). However, the proportion of cells displaying apoptotic features such as nuclear fragmentation, DNA fragmentation, and reactive oxygen species (ROS) production were increased more in the WT strain during the chronic SAC activation compared to slx5Δ, indicating that Slx5 may be involved in the chronic SAC-activation-apoptosis relation. We also showed that the possible role of Slx5 in the chronic SAC activation-apoptosis association was not through ubiquitin dependent degradation of 3 apoptosis-related and sumoylated candidate proteins.
    Keywords:  Saccharomyces cerevisiae; apoptosis; cancer; prolonged mitotic arrest; spindle assembly checkpoint
    DOI:  https://doi.org/10.3906/biy-1812-46
  14. Life Sci. 2019 Jul 12. pii: S0024-3205(19)30581-8. [Epub ahead of print] 116655
    MitoQ ameliorates testicular damage induced by gamma irradiation in rats: Modulation of mitochondrial apoptosis and steroidogenesis.
    Ayman A Ibrahim, Heba M Karam, Esmat A Shaaban, Marwa M Safar, Mohammed F El-Yamany.
      AIMS: The deleterious effect of gamma radiation on testicular tissue is a challenging problem in nuclear medicine. This study investigated the potential radioprotective effect of mitoquinol (MitoQ), a mitochondria-targeted antioxidant, against testicular damage induced by gamma irradiation in rats.MAIN METHODS: Rats were allocated into four groups. The first group served as the control, the second group received MitoQ (2 mg / kg / day; i.p.) for seven days, the third group was exposed to gamma radiation (5 Gy as a single dose) and the last group received MitoQ prior to irradiation. Rats were sacrificed. Then, sperm analyses and the serum testosterone were determined. Moreover, evaluation of mitochondrial oxidative stress parameters (SOD, GSH and GPx) as well as apoptosis indicators (cytochrome-c, Bax, Bcl-2 and caspase-3) was performed. Additionally, analysis of steroidogensis biomarkers (StAR, 3β-HSD and 17β-HSD) and histopathological investigations were carried out.
    KEY FINDINGS: MitoQ replenished mitochondrial SOD, GPx and GSH indicating its strong antioxidant effect in addition to its energy preservation manifested by the elevated ATP. MitoQ inhibited the intrinsic apoptosis via diminution of Bax, cytochrome-c and caspase-3 and alleviation of Bcl-2. This antioxidant conferred protection to steroidogenesis as verified by the increase in testosterone and the up-regulation of StAR, 3β-HSD and 17β-HSD expression; these effects might be correlated with its antioxidant/anti-apoptotic potential. Histopathological and sperm analyses corroborated the biochemical findings.
    SIGNIFICANCE: This study identifies MitoQ as a novel agent for the management of testicular toxicity induced by gamma irradiation.
    Keywords:  Gamma radiation; Mitochondria-targeted antioxidant; Mitochondrial apoptosis; Steroidogenesis; Testicular damage
    DOI:  https://doi.org/10.1016/j.lfs.2019.116655
  15. Mol Med Rep. 2019 Jul 11.
    Bavachinin exhibits antitumor activity against non‑small cell lung cancer by targeting PPARγ.
    Lu-Na Ge, Lei Yan, Cheng Li, Kai Cheng.
      Bavachinin (BNN), one of the main active ingredients of Psoraleacorylifolia, can activate peroxisome proliferator‑activated receptor γ (PPARγ). PPARγ has become a promising therapeutic target in cancer. The aim of the present study was to explore the antitumor effects of BNN in non‑small cell lung cancer (NSCLC). Cell Counting Kit‑8 and lactate dehydrogenase release assays were performed to measure cell toxicity. Western blotting and immunofluorescence were used to analyze the expression of apoptosis‑related factors and PPARγ. The ability of PPARγ to bind to BNN was evaluated by drug affinity responsive target stability (DARTS) and cellular thermal shift assay (CETSA). A reactive oxygen species (ROS) assay kit was used to detect the ROS level. The results revealed that the survival rates and cell viability of A549 cells were reduced by BNN in a dose‑dependent manner. The present results also demonstrated that BNN dose‑dependently changed the expression of Bcl‑2, Bax, caspases‑3/9 and PPARγ. In addition, through the cytotoxic and anti‑proliferative effects, the apoptosis‑related proteins' inhibitive properties of BNN were completely inhibited by the PPARγ antagonists T0070907 and GW9662. The DARTS and CETSA results confirmed the protein binding activity of PPARγ. Furthermore, it was demonstrated that the BNN‑induced ROS generation was dependent on PPARγ activation. Taken together, the present study demonstrated that BNN induced the death of A549 cells by activating PPARγ, an effect mediated by the increased ROS level. These results highlighted the potential role of BNN as a chemotherapeutic agent against NSCLC.
    DOI:  https://doi.org/10.3892/mmr.2019.10485
  16. Med Sci Monit. 2019 Jul 16. 25 5280-5288
    Apigenin Protects Against Renal Tubular Epithelial Cell Injury and Oxidative Stress by High Glucose via Regulation of NF-E2-Related Factor 2 (Nrf2) Pathway.
    Jichen Zhang, Xuemei Zhao, Hongling Zhu, Jingnan Wang, Junhua Ma, Mingjun Gu.
      BACKGROUND Diabetic nephropathy (DN) is a disease characterized by oxidative stress and apoptosis of renal tubular epithelial cells driven by hyperglycemia. Apigenin is a flavonoid compound that possesses potent anti‑apoptotic properties. The present study aimed to explore the protective effects and underlying mechanisms of apigenin on renal tubular epithelial cells exposed to hyperglycemia. MATERIAL AND METHODS Human renal epithelial cell HK-2 were incubated to D-glucose to establish in vitro DN model. The cell viability, lactate dehydrogenase (LDH) release, apoptosis and oxidative stress were evaluated. qRT-PCR was performed to determine the mRNA levels of NF-E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Western blot analysis was performed to measure the protein expressions of Nrf2. RESULTS In HK-2 cells, high glucose reduced cell viability in a concentration- and time-dependent manner. Apigenin suppressed the decrease in cell viability and increase in supernatant LDH release at 100 and 200 μM after 48-h treatment. Apigenin reduced apoptotic rate and pro-inflammatory cytokines production. Apigenin suppressed oxidative stress and increased mRNA expressions of Nrf2 and HO-1. Inhibition of Nrf2 using small interfering RNA (siRNA), or cotreatment with LY294002, an inhibitor of PI3K/Akt, abolished the protective effect on high glucose-induced injury, oxidative stress, and pro-inflammatory cytokines production by apigenin. LY294002 also attenuated the increase in Nrf2 protein by apigenin in high glucose-treated HK-2 cells. CONCLUSIONS Apigenin protects renal tubular epithelial cells against high glucose-induced injury through suppression of oxidative stress and inflammation via activation of the Nrf2 pathway.
    DOI:  https://doi.org/10.12659/MSM.915038
  17. Anal Cell Pathol (Amst). 2019 ;2019 5853426
    Recombinant α-Klotho Protein Alleviated Acute Cardiorenal Injury in a Mouse Model of Lipopolysaccharide-Induced Septic Cardiorenal Syndrome Type 5.
    Xi Liu, Yangyang Niu, Xiaoqin Zhang, Yingying Zhang, Ying Yu, Jieli Huang, Jiangtao Li, Chen Yu.
      Background and Aims: Klotho is an aging-suppressor gene mainly expressed in the renal tubules. The klotho gene encodes the α-klotho protein, which has many functions. Previous studies have found that α-klotho protein has a cardiorenal protective function. α-Klotho deficiency renders the kidney more susceptible to injury and results in cardiovascular calcification and left ventricular hypertrophy in chronic kidney disease. However, the role of α-klotho in acute heart injury and acute kidney injury with sepsis remains unknown. This study aimed to investigate the effects and mechanisms of α-klotho in septic cardiorenal injury.Methods: Male 8-week-old C57BL/6 mice were randomly assigned to the control group, lipopolysaccharide (LPS; 10 mg/kg) group, LPS (10 mg/kg)+α-klotho (0.01 mg/kg) group, and LPS (10 mg/kg)+α-klotho (0.02 mg/kg) group. Recombinant α-klotho was intraperitoneally injected an hour before LPS injection. Mice were euthanized at 24 h after LPS injection. The serum troponin, brain natriuretic peptide (BNP), neutrophil gelatinase-associated lipocalin (NGAL), and creatinine levels were measured in all groups at 24 h. Biomarkers of mice heart apoptosis, inflammation, oxidative stress, and endoplasmic reticulum stress, such as caspase-3, interleukin 1 (IL-1), reactive oxygen species (ROS), and glucose-regulated protein 78 (GRP78), were also measured.
    Results: α-Klotho was mainly expressed in mice kidneys and was undetectable in the control mice hearts. α-Klotho substantially decreased after LPS injection. In the LPS group, the serum troponin levels significantly increased as early as 6 h (p < 0.05) after LPS injection, while the BNP, NGAL, and creatinine levels significantly increased at 24 h (p < 0.05). Pretreatment with α-klotho significantly ameliorated acute cardiorenal injury. In the LPS+α-klotho (0.01 mg/kg) group, the levels of apoptosis, inflammation, and oxidative stress were decreased, while the level of endoplasmic reticulum stress was elevated.
    Conclusions: α-Klotho significantly alleviates acute cardiorenal injury in LPS-induced septic cardiorenal injury due to the inhibition of apoptosis, inflammation, and oxidation, as well as the regulation of endoplasmic reticulum stress levels.
    DOI:  https://doi.org/10.1155/2019/5853426
  18. PeerJ. 2019 ;7 e7192
    Curcumin ameliorates atrophy of seminal vesicle via reduction of oxidative stress in castrated mice.
    Rui Li, Hao Li, Ke Rao, Kang Liu, Yan Zhang, Xiaming Liu, Tao Wang, Shaogang Wang, Zhuo Liu, Jihong Liu.
      Background: The growth and function of seminal vesicle are dependent on androgen. This study was conducted to investigate the role of oxidative stress in castration-induced seminal vesicle atrophy and to explore the effects of curcumin, an antioxidant extracted from rhizome of turmeric, on seminal vesicle of castrated mice.Methods: C57BL/6J mice were randomly divided into three groups: control, castration, and castration with curcumin (n = 10 for each group). After surgical castration, mice in the curcumin treatment group received intragastric administration of curcumin at 100 mg/kg body weight for 4 weeks, whereas mice in the other two groups were treated with olive oil. After that, the body weight, seminal vesicle weight and serum testosterone of mice were measured. Apoptosis and oxidative stress levels in seminal vesicle were also determined.
    Results: After castration, both the weight and size of seminal vesicle decreased dramatically. The expression of three NADPH oxidase (NOX) subtypes: NOX1, NOX2 and NOX4, increased in seminal vesicle of castrated mice, resulting in high level oxidative stress. The ratio of Bax to Bcl-2 was also elevated after castration, accompanied by enhanced caspase3 activity. Additionally, castration increased the number of apoptotic cells in seminal vesicle. Curcumin treatment could inhibit the expression of NOX1, NOX2 and NOX4, decreasing oxidative stress and apoptosis. The atrophy of seminal vesicle caused by castration was ameliorated by curcumin.
    Conclusion: Castration could cause atrophy of seminal vesicle probably via inducing oxidative stress. Curcumin treatment could reduce the oxidative stress in seminal vesicle by decreasing the expression of NOX1, NOX2 and NOX4, thereby ameliorating apoptosis and atrophy of seminal vesicle. Oxidative stress might play a role in castration-induced seminal vesicle atrophy.
    Keywords:  Castration; Curcumin; Oxidative stress; Seminal vesicle
    DOI:  https://doi.org/10.7717/peerj.7192
  19. Curr Med Chem. 2019 Jul 12.
    Targeting mitochondria through the use of mitocans as emerging anticancer agents.
    Ioana Macasoi, Alexandra Mioc, Marius Mioc, Irina Soica, Adelina Chevereșan, Cristina Dehelean, Victor Dumitrașcu.
      Mitochondria are key players with a multi-functional role in many vital cellular processes, such as energy metabolism, redox regulation, calcium homeostasis, reactive oxygen species (ROS) as well as in cell signaling, survival and apoptosis. These functions are mainly regulated through important enzyme signaling cascades, which if altered may influence the outcome of cell viability and apoptosis. Therefor some of the key enzymes that are vital for these signaling pathways are emerging as important targets for new anticancer agents development. Mitocans are compounds aimed at targeting mitochondria in cancer cells by altering mitochondrial functions thus causing cell growth inhibition or apoptosis. This review summarizes the until present known classes of mitocans, their mechanism of action and potential therapeutic use in different forms of cancer.
    Keywords:  Bcl-2; cancer; electron transport chain; hexokinase; lactate dehydrogenase; mithocondria; mitocans; pyruvate dehydrogenase kinase
    DOI:  https://doi.org/10.2174/0929867326666190712150638
  20. Environ Toxicol. 2019 Jul 16.
    Protective effects of hepatocyte growth factor gene overexpression against hydrogen peroxide-induced apoptosis in mesenchymal stem cells.
    Yong Jun Choi, Chang Min Lee, Jeong Hyun Lee, See-Hyoung Park, Myeong Jin Nam.
      Hepatocyte growth factor (HGF) has recently been reported to exhibit antioxidant and antiapoptotic effects. Therefore, we investigated the effect of overexpression of HGF gene in H2 O2 -treated mesenchymal stem cells (MSCs). HGF-overexpression increased the cell viability from 50% to 84%, decreased the population of apoptotic cells from 20% to 16%, and decreased the intracellular reactive oxygen species (ROS) levels from 127% to 100% in cells treated with H2 O2 . HGF suppression decreased the cell viability from 58% to 36%, increased the population of apoptotic cells from 23 to 81%, and increased the intracellular ROS levels from 181% to 240% in cells exposed to H2 O2 . HGF-overexpression also reduced the expression levels of proapoptotic proteins in MSCs treated with H2 O2 . Phosphorylation of extracellular signal-regulated kinases, c-Jun amino-terminal kinases, and p38, which was induced by H2 O2 , decreased in MSCs overexpressing the HGF gene. Taken together, our results suggest that HGF has a protective effect on H2 O2 -induced apoptosis in MSCs.
    Keywords:  CRISPR; hepatocyte growth factor; mesenchymal stem cell; reactive oxygen species
    DOI:  https://doi.org/10.1002/tox.22824
  21. Hum Exp Toxicol. 2019 Jul 18. 960327119864160
    Testicular toxicity of gentamicin in adult rats: Ameliorative effect of lycopene.
    Haa Aly.
      The current study was aimed to investigate the ameliorative effect of lycopene against gentamicin-induced testicular toxicity in adult rat testes. Pretreatment with lycopene (4 mg/kg/day) significantly prevented the decrease in the absolute testes weight and relative testes weight and the reduction in sperm count, motility, viability, and daily sperm production in gentamicin (100 mg/kg/day)-treated rats. Gentamicin significantly decreased the level of serum testosterone and testicular lactate dehydrogenase-X and G6PDH activities but a marked increase was observed upon pretreatment with lycopene. Testicular caspase-3 and -9 activities were significantly increased but lycopene showed significant protection from gentamicin-induced apoptosis. Oxidative stress was induced by gentamicin treatment as evidenced by increased hydrogen peroxide level and lipid peroxidation and decreased the antioxidant enzymes superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase activities and glutathione content. These alterations were effectively prevented by lycopene pretreatment. Histopathological examination showed loss of spermatogenesis and morphological abnormalities of the testis after treatment with gentamycin. These abnormalities were effectively normalized by pretreatment with lycopene. In conclusion, gentamicin decreases rat testes weight and inhibits spermatogenesis. It induces oxidative stress and apoptosis by possible mitochondrial dysfunction. These data provide insight into the mode of action of gentamicin-induced testicular toxicity and the beneficial role provided by lycopene to restore the suppressed spermatogenesis.
    Keywords:  Gentamicin; apoptosis; lycopene; oxidative stress; sperm; testis
    DOI:  https://doi.org/10.1177/0960327119864160
  22. Respir Physiol Neurobiol. 2019 Jul 10. pii: S1569-9048(19)30118-1. [Epub ahead of print] 103252
    Paeonol protects mitochondrial injury and prevents pulmonary vascular remodeling in hypoxia.
    Dapeng Wang, Yali Du, Hongyang Xu, Hong Pan, Ruilan Wang.
      Mitochondrial injury of pulmonary artery smooth muscle cells (PASMCs) is an important stage in the development of pulmonary arterial hypertension (PAH). Recent studies revealed that Paeonol exerts anti-proliferative effects on vascular smooth muscle cells. However, whether Paeonol is directly involved in mitochondrial injury related to PAH remains unknown. Here, we found that hypoxia-induced mitochondrial injury in vivo was alleviated in the presence of Paeonol. Hypoxia mediated the mitochondrial injuries in PASMCs in vitro, including decreased ATP generation, morphological alterations, mitochondrial polarization and increased reactive oxygen species production, which were suppressed by Paeonol. Our results also indicated that the expression of peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α) was regulated by Paeonol. Paeonol caused significant alterations in mitochondrion-dependent apoptosis through PGC-1α in PASMCs. Taken together, these results provide the first evidence confirming the protective effect of Paeonol in mediating mitochondrial injury under hypoxia and elucidating the necessary role of PGC-1α in the effects of Paeonol in inducing PASMC apoptosis.
    Keywords:  Apoptosis; Mitochondria; Paeonol; Peroxisome proliferator-activated receptor-gamma co-activator 1α; Pulmonary artery smooth muscle cells
    DOI:  https://doi.org/10.1016/j.resp.2019.103252
  23. Biochem Biophys Res Commun. 2019 Jul 10. pii: S0006-291X(19)31206-9. [Epub ahead of print]
    Typhaneoside prevents acute myeloid leukemia (AML) through suppressing proliferation and inducing ferroptosis associated with autophagy.
    Hai-Yan Zhu, Zong-Xuan Huang, Guo-Qi Chen, Fen Sheng, Yin-Suo Zheng.
      Leukemia remains a fatal disease for most patients and effective therapeutic strategies are urgently required. Typhaneoside (TYP) is a major flavonoid in the extract of Pollen Typhae, showing significant biological and pharmacological effects. In the present study, we explored the effects of TYP on acute myeloid leukemia (AML) progression. The results indicated that TYP markedly reduced the cell viability of AML cells and arrested the cell cycle at the G2/M phase by regulating the expression of associated proteins. In addition, TYP significantly induced apoptosis in AML cells by promoting the activation of Caspase-3. Intracellular and mitochondrial reactive oxygen species (ROS) accumulation were highly detected in AML cells after treatment with TYP. Moreover, TYP clearly induced ferroptosis in AML cells, and this process was iron-dependent and attendant with mitochondrial dysfunction. We also found that TYP significantly triggered autophagy in AML cells by promoting the activation of AMP-activated protein kinase (AMPK) signaling, contributing to ferritin degradation, ROS accumulation and ferroptotic cell death ultimately. In conclusion, the findings above provided solid evidences that TYP could be a promising therapeutic agent to prevent AML progression by inducing apoptosis, ROS production, autophagy and ferroptosis.
    Keywords:  Acute myeloid leukemia (AML); Autophagy; Ferroptosis; ROS accumulation; Typhaneoside (TYP)
    DOI:  https://doi.org/10.1016/j.bbrc.2019.06.070
  24. Front Pharmacol. 2019 ;10 733
    C-Phycocyanin Ameliorates Mitochondrial Fission and Fusion Dynamics in Ischemic Cardiomyocyte Damage.
    Jinchao Gao, Lidong Zhao, Jinfeng Wang, Lihang Zhang, Dandan Zhou, Jinlong Qu, Hao Wang, Ming Yin, Jiang Hong, Wenjuan Zhao.
      Mitochondrial dysfunction is a predominant risk factor in ischemic heart disease, in which the imbalance of mitochondrial fusion and fission deteriorates mitochondrial function and might lead to cardiomyocyte death. C-phycocyanin (C-pc), an active component from blue-green algae, such as Spirulina platensis, has been reported to have anti-apoptosis and anti-oxidation functions. In this study, the effects of C-pc on mitochondrial dynamics of cardiomyocytes was examined using an oxygen-glucose deprivation/reoxygenation (OGD/R) model in H9c2 cells, an in vitro model to study the ischemia in the heart. Cell viability assay showed that C-pc dose-dependently reduced OGD/R-induced cell death. Intracellular reactive oxygen species production induced by OGD/R was decreased in C-pc-treated groups in a dose-dependent manner as well. H9c2 cells subjected to OGD/R showed excessive mitochondrial fission and diminished mitochondrial fusion. C-pc treatment significantly ameliorated unbalanced mitochondrial dynamics induced by OGD/R and regulated mitochondrial remodeling through inhibiting mitochondrial fission while promoting fusion. The enhanced expressions of dynamin 1-like protein and mitochondrial fission 1 protein induced by OGD/R were suppressed by C-pc, while the subdued expressions of mitochondrial fusion proteins mitofusins 1 and 2 and optic atrophy 1 induced by OGD/R increased in C-pc-treated groups. Triple immunofluorescence staining revealed that C-pc treatment reduced the recruitment of dynamin 1-like protein from cytoplasm to mitochondrial membranes. Furthermore, C-pc protected H9c2 cells against OGD/R-induced cytochrome c/apoptotic protease activating factor-1 intrinsic apoptosis and suppressed the phosphorylations of extracellular signal-regulated kinase and c-Jun N-terminal kinase. These results suggest that C-pc protects cardiomyocytes from ischemic damage by affecting mitochondrial fission and fusion dynamics and reducing apoptosis and, thus, may be of potential as a prophylactic or therapeutic agent for ischemic heart disease.
    Keywords:  C-phycocyanin; apoptosis; cardiomyocytes; fission; fusion; ischemia; mitochondrial dynamics
    DOI:  https://doi.org/10.3389/fphar.2019.00733
  25. Invest Ophthalmol Vis Sci. 2019 Jul 01. 60(8): 3034-3045
    Retinal Pigment Epithelium Cell Death Is Associated With NLRP3 Inflammasome Activation by All-trans Retinal.
    Yi Liao, Houjian Zhang, Danxue He, Yan Wang, Binxiang Cai, Jingmeng Chen, Jianxing Ma, Zuguo Liu, Yalin Wu.
      Purpose: Visual (retinoid) cycle anomalies induce aberrant build-up of all-trans retinal (atRAL) in the retinal pigment epithelium (RPE), which is a cause of RPE atrophy in Stargardt disease type 1 and age-related macular degeneration. NLR family pyrin domain containing 3 (NLRP3) inflammasome activation is implicated in the etiology of age-related macular degeneration. Here, we elucidated the relationship between NLRP3 inflammasome activation and atRAL-induced death of RPE cells.Methods: Cellular toxicities were assessed by MTS or MTT assays. Expression levels of mRNAs and proteins were determined by quantitative reverse transcription-polymerase chain reaction, Western blotting, or enzyme-linked immunosorbent assay. Fluorescence microscopy was used to examine intracellular signals. Ultrastructural features of organelles were examined by transmission electron microscope.
    Results: Abnormal accumulation of atRAL was associated with a significant increase in the proportion of human ARPE-19 cells exhibiting features of apoptosis and Caspase-3/gasdermin E (GSDME)-mediated pyroptosis. These cells also exhibited elevated expression of NLRP3, ASC, cleaved Caspase-1/poly ADP-ribose polymerase (PARP)/Caspase-3/GSDME, interleukin-1β (IL-1β), and IL-18, as well as NLRP3 inflammasome-related genes (IL1B and IL18). After exposure of human ARPE-19 cells to excess atRAL, reactive oxygen species (ROS) (including mitochondrial ROS) and cathepsins released from lysosomes transmitted signals leading to NLRP3 inflammasome activation. Suppressing the production of ROS, NLRP3 inflammasome, Caspase-1, cathepsin B, or cathepsin D protected ARPE-19 cells against atRAL-associated cytotoxicity. Damage to mitochondria, lysosomes, and endoplasmic reticulum in atRAL-exposed ARPE-19 cells was partially alleviated by treatment with MCC950, a selective NLRP3 inflammasome inhibitor.
    Conclusions: Aberrant build-up of atRAL promotes the death of RPE cells via NLRP3 inflammasome activation.
    DOI:  https://doi.org/10.1167/iovs.18-26360
  26. Cell Death Dis. 2019 Jul 17. 10(8): 542
    Propofol directly induces caspase-1-dependent macrophage pyroptosis through the NLRP3-ASC inflammasome.
    Lingbin Sun, Wei Ma, Wenli Gao, Yanmei Xing, Lixin Chen, Zhengyuan Xia, Zhongjun Zhang, Zhongliang Dai.
      Propofol infusion syndrome (PRIS) is an uncommon life-threatening complication observed most often in patients receiving high-dose propofol. High-dose propofol treatment with a prolonged duration can damage the immune system. However, the associated molecular mechanisms remain unclear. An increasing number of clinical and experimental observations have demonstrated that tissue-resident macrophages play a critical role in immune regulation during anaesthesia and procedural sedation. Since the inflammatory response is essential for mediating propofol-induced cell death and proinflammatory reactions, we hypothesised that propofol overdose induces macrophage pyroptosis through inflammasomes. Using primary cultured bone marrow-derived macrophages, murine macrophage cell lines (RAW264.7, RAW-asc and J774) and a mouse model, we investigated the role of NLRP3 inflammasome activation and secondary pyroptosis in propofol-induced cell death. We found that high-dose propofol strongly cleaved caspase-1 but not caspase-11 and biosynthesis of downstream interleukin (IL)-1β and IL-18. Inhibition of caspase-1 activity blocks IL-1β production. Moreover, NLRP3 deletion moderately suppressed cleaved caspase-1 as well as the proportion of pyroptosis, while levels of AIM2 were increased, triggering a compensatory pathway to pyroptosis in NLRP3-/- macrophages. Here, we show that propofol-induced mitochondrial reactive oxygen species (ROS) can trigger NLRP3 inflammasome activation. Furthermore, apoptosis-associated speck-like protein (ASC) was found to mediate NLRP3 and AIM2 signalling and contribute to propofol-induced macrophage pyroptosis. In addition, our work shows that propofol-induced apoptotic initiator caspase (caspase-9) subsequently cleaved effector caspases (caspase-3 and 7), indicating that both apoptotic and pyroptotic cellular death pathways are activated after propofol exposure. Our studies suggest, for the first time, that propofol-induced pyroptosis might be restricted to macrophage through an NLRP3/ASC/caspase-1 pathway, which provides potential targets for limiting adverse reactions during propofol application. These findings demonstrate that propofol overdose can trigger cell death through caspase-1 activation and offer new insights into the use of anaesthetic drugs.
    DOI:  https://doi.org/10.1038/s41419-019-1761-4
  27. Artif Cells Nanomed Biotechnol. 2019 Dec;47(1): 2737-2745
    Green synthesis of gold nanoparticles using a Cordyceps militaris extract and their antiproliferative effect in liver cancer cells (HepG2).
    Yujiang Ji, Yang Cao, Yong Song.
      Hepatocellular carcinoma is the most common liver cancer among different types of cancers. Cordyceps Militaris mushroom species traditionally used as an alternative medicine in china for centuries. Gold nanoparticles plays vital role in the development of the anticancer drugs. In our research, we investigated the gold nanoparticles with C. Militaris on the hepatocellular carcinoma HepG2 cells. The synthesized gold nanoparticles stability and integrity was studied at different time intervals. The gold nanoparticles potentially halt the growth of the HepG2 cells at the IC50 concentration between 10 μg and 12.5 μg/ml. The HR-TEM and XRD revealed the size and shape of the synthesized gold nanoparticles. The size of the gold nanoparticles was about 15 20 nm and the shape of gold nanoparticles was face-center-cubic structure. The FT-IR results proved that the gold nanoparticles contain hydroxyl and alkynes groups. The gold nanoparticles extract develops ROS and cause damage to the mitochondrial membrane potential in the hepatocellular carcinoma HepG2 cells. The gold nanoparticles extract tends to initiate the apoptosis by activating the Bax, Bid, caspases and inhibits the activation anti-apoptotic bcl-2 in the HepG2 cells. Our results concluded that the gold nanoparticles with C. Militaris would be an efficient chemotherapeutic drug against the hepatocellular carcinoma cells.
    Keywords:  ; HepG2 cells; apoptosis; gold nanoparticles; reactive oxygen species
    DOI:  https://doi.org/10.1080/21691401.2019.1629952
  28. Avicenna J Phytomed. 2019 Jul-Aug;9(4):9(4): 347-361
    Effect of crocin on biochemical parameters, oxidative/antioxidative profiles, sperm characteristics and testicular histopathology in streptozotocin-induced diabetic rats.
    Seyed Mersad Sefidgar, Mahmood Ahmadi-Hamedani, Ashkan Jebelli Javan, Reza Narenji Sani, Abbas Javaheri Vayghan.
      Objective: Chronic hyperglycemia and overproduction of reactive oxygen species (ROS) are strong predictors of the development of reproductive complications of diabetes. The present study was conducted to determine the effects of crocin on biochemical parameters, oxidative stress, and sperm characteristics as well as testes histopathology in diabetic rats.Materials and Methods: Twenty-four rats were divided into the four groups as follows: control, untreated diabetic and two crocin (40 and 60 mg/kg/day)-treated diabetic groups. Diabetes was induced by injection of a single dose of streptozotocin (STZ, 60 mg/kg). Administration of crocin (intraperitoneally) was started three days after STZ injection and was continued until the 28th day. At the end of the experiment, rats were anesthetized after weighing. Blood samples and epididymal sperm were subsequently collected to measure biochemical parameters (glucose and lipid profile), total oxidant and antioxidant status (TOS and TAS, respectively), oxidative stress index (OSI), and sperm characteristics (count, motility, and viability); also, testes were dissected out for histopathology examination.
    Results: Our result indicated that blood glucose, cholesterol, triglyceride, LDL cholesterol levels, as well as TOS, and OSI decreased, but body weight, sperm counts, motility and viability, as well as TAS and HDL levels increased significantly in the crocin-treated diabetic rats (P˂0.05). In testis sections from diabetic rats treated with crocin (40 and 60 mg/kg), seminiferous tubules exhibited normal shape and restoration of testis architecture was observed.
    Conclusion: Administration of crocin in the present study, ameliorated blood glucose, lipid abnormalities, oxidative stress, sperm characteristics and testis damage in STZ-diabetic rats.
    Keywords:  Biochemical parameters; Crocin; Oxidative stress index; Sperm characteristics; Streptozotocin; Testicular histopathology
  29. Drug Des Devel Ther. 2019 ;13 2153-2167
    Novel peptide myristoly-CM4 induces selective cytotoxicity in leukemia K562/MDR and Jurkat cells by necrosis and/or apoptosis pathway.
    Huidan Zhang, Dongju Han, Tongtong Lv, Kehang Liu, Yunqing Yang, Xixi Xu, Yuqing Chen.
      Purpose: There is an urgent need for the development of novel, effective, and less toxic drugs to treat leukemia. Antimicrobial peptides (AMPs) have received much more attention as alternative chemotherapeutic agents. This study aimed to examined the cytotoxicity of a novel AMP myristoly-CM4 against chronic myeloid leukemia cells (K562/MDR) and acute lymphocytic leukemia cells (Jurkat), and further investigated its selectivity to clarify the cytotoxic mechanism. Materials and methods: In this study, the cytotoxicity and selectivity of myristoly-CM4 against K562/MDR and Jurkat cells were assessed in vitro, and the anticancer mechanism responsible for its cytotoxicity and selectivity was further investigated. Results: Myristoly-CM4 was cytotoxic to these leukemia cell lines (IC50 2-4 μM) and was less cytotoxic to normal cells (HEK-293, L02 cells, peripheral blood mononuclear cells, and erythrocytes). Myristoyl-CM4 had stronger affinity to K562/MDR and Jurkat cells than to normal cells, while the contents of phosphatidylserine and sialic acids on the cell surfaces of K562/MDR and Jurkat cells were significantly higher than that of HEK293 cells. The myristoyl group effectively mediated the internalization of myristoyl-CM4 to leukemia cells. After internalization, myristoyl-CM4 could target mitochondria and affected mitochondrial function, including disruption of Δψm, increasing the accumulation of ROS, increasing the Bax/Bcl-2 ratio, activating caspase 9 and 3, and PARP to induce mitochondria-dependent apoptosis in both K562/MDR and Jurkat cells. Myristoyl-CM4 also induced K562/MDR cell necrosis by directive membrane disruption, and significantly decreased the level of P-glycoprotein in K562/MDR cells. Conclusion: These results suggested that myristoyl-CM4 showed selective cytotoxicity to leukemia K562/MDR and Jurkat cells by apoptosis and/or necrosis pathway. Myristoyl-CM4, thus, appears to be a promising candidate for leukemia treatment, including multidrug-resistant leukemia.
    Keywords:  apoptosis; leukemia; multi-drug resistance; myristoyl-CM4; necrosis; selectivity
    DOI:  https://doi.org/10.2147/DDDT.S207224
  30. Arch Physiol Biochem. 2019 Jul 17. 1-8
    Hepatoprotective effects of ethyl pyruvate against carbon tetrachloride-induced oxidative stress, biochemical and histological alterations in rats.
    Miraç Bakdemir, Ebru Çetin.
      This study investigated the protective effects of ethyl pyruvate (EP) against carbon tetrachloride (CCl4)-induced acute hepatic injury in rats. The administration of a single dose of CCl4 (1.6 g/kg body weight) significantly elevated the levels of malondialdehyde, nitric oxide, alanine transaminase, aspartate transaminase, and alkaline phosphatase, cholesterol, low-density lipoprotein cholesterol, and triglycerides. In addition, CCl4 was found to significantly suppress the activity of superoxide dismutase, catalase, and glutathione peroxidase. All of these parameters were restored to their normal levels by the administration of EP before and after the CCl4 injection. Moreover, the number of positive apoptotic hepatocytes had significantly increased in the CCl4 group but decreased in rats treated with EP along with CCl4. Histopathological changes induced by CCl4 were also ameliorated by EP treatment. These findings provided evidence that EP, because of its antioxidant and anti-apoptotic action, could protect rat liver against CCl4-induced acute liver injury.
    Keywords:  Antioxidant; apoptosis; carbon tetrachloride; ethyl pyruvate; liver injury
    DOI:  https://doi.org/10.1080/13813455.2019.1640254
  31. In Vitro Cell Dev Biol Anim. 2019 Jul 16.
    β-carotene improves oocyte development and maturation under oxidative stress in vitro.
    Shuai Yu, Yong Zhao, Yanni Feng, Hongfu Zhang, Lan Li, Wei Shen, Minghui Zhao, Lingjiang Min.
      Recently, the mean maternal age at first birth has been continuing to increase. The decline in the age-related fertility is due to the reduction in the number and the quality of the oocyte. An elevation in intra-ovarian reactive oxygen species (ROS) is correlated with the increase in maternal age, and the oxidative stress is involved in the decline in oocyte quality. Although β-carotene, a very effective quencher of ROS, has been found to have the beneficial contribution to the ovarian development and steroidogenesis, it is unknown the effect of β-carotene on the oocyte development especially oocyte maturation. This investigation aimed to explore the beneficial contribution of β-carotene on oocyte maturation under oxidative stress and the underlying mechanism. We found that the oxidative stress induced by ROS reagent Rosup inhibited oocyte development/maturation and parthenogenetic activation which could be dramatically rescued by β-carotene (57.1 ± 4.7% vs 78.9 ± 3.8%; p < 0.05) in vitro. The underlying mechanisms include that β-carotene not only reduces ROS formation and cell apoptosis, but also it can restore actin expression, cortical granule-free domain (CGFD) formation, mitochondria homogeneous distribution, and nuclear maturation. The data suggest that β-carotene acts as a potential antioxidant in the oocyte. Therefore, the findings from this investigation provide the fundamental 7knowledge for using β-carotene as an antioxidant to improve the oocyte quality and even the ovarian function.
    Keywords:  Antioxidant; Maturation; Oocyte; Oxidative stress; β-Carotene
    DOI:  https://doi.org/10.1007/s11626-019-00373-0
  32. Acta Pharmacol Sin. 2019 Jul 17.
    WX20120108, a novel IAP antagonist, induces tumor cell autophagy via activating ROS-FOXO pathway.
    Rui Ding, Xin Wang, Wei Chen, Zhi Li, Ai-Li Wei, Qing-Bin Wang, Ai-Hua Nie, Li-Li Wang.
      Recently, inhibitor of apoptosis proteins (IAPs) and some IAP antagonists were found to regulate autophagy, but the underlying mechanisms remain unclear. WX20120108 is an analogue of GDC-0152 (a known IAP antagonist) and displays more potent anti-tumor and autophagy-regulating activity in tumor cells, we investigated the regulatory mechanisms underlying WX20120108-induced autophagy. Using molecular docking and fluorescence polarization anisotropy (FPA) competitive assay, we first demonstrated that WX20120108, acting as an IAP antagonist, bound to the XIAP-BIR3, XIAP BIR2-BIR3, cIAP1 BIR3, and cIAP2 BIR3 domains with high affinities. In six cancer cell lines, WX20120108 inhibited the cell proliferation with potencies two to ten-fold higher than that of GDC-0152. In HeLa and MDA-MB-231 cells, WX20120108 induced caspase-dependent apoptosis and activated TNFα-dependent extrinsic apoptosis. On the other hand, WX20120108 induced autophagy in HeLa and MDA-MB-231 cells in dose- and time-dependent manners. We revealed that WX20120108 selectively activated Foxo3, evidenced by Foxo3 nuclear translocation in both gene modified cell line and HeLa cells, as well as the upregulated expression of Foxo3-targeted genes (Bnip3, Pik3c3, Atg5, and Atg4b), which played a key role in autophagy initiation. WX20120108-induced autophagy was significantly suppressed when Foxo3 gene was silenced. WX20120108 dose-dependently increased the generation of reactive oxygen species (ROS) in HeLa cells, and WX20120108-induced Foxo3 activation was completely blocked in the presence of catalase, a known ROS scavenger. However, WX20120108-induced ROS generation was not affected by cIAP1/2 or XIAP gene silencing. In conclusion, WX20120108-induced autophagy relies on activating ROS-Foxo3 pathway, which is independent of IAPs. This finding provides a new insight into the mechanism of IAP antagonist-mediated regulation of autophagy.
    Keywords:  Foxo3; GDC-0152; IAP antagonists; ROS; WX20120108; apoptosis; autophagy; carcinoma cells; catalase
    DOI:  https://doi.org/10.1038/s41401-019-0253-5
  33. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2019 Jun;31(6): 756-761
    [Effects of short-chain acyl-CoA dehydrogenase on human umbilical vein endothelial cell apoptosis].
    Zhonghong Li, Zhaohui Shu, Yingqin Liao, Peiqing Liu, Jing Lu, Ping Wang, Guixiang Wang, Linquan Zang, Sigui Zhou.
      OBJECTIVE: To observe the changes of short-chain acyl-CoA dehydrogenase (SCAD) expression on human umbilical vein endothelial cell (HUVEC) apoptosis and investigate its relationship with apoptosis.METHODS: The HUVEC was cultured normally for 2-3 days. The apoptotic model of HUVEC was established by tert-butyl hydrogen peroxide (tBHP). The HUVEC was treated by different concentrations of tBHP (0, 10, 20, 30, 40, 50 μmol/L) for 12 hours and different time (0, 3, 6, 9, 12 hours) with 50 μmol/L tBHP to establish the apoptotic model of HUVEC. The cell viability was detected by methyl thiazolyl tetrazolium (MTT), the mRNA expression of SCAD was determined by real-time polymerase chain reaction (PCR), the protein expression of SCAD was achieved by Western Blot. The best concentrate and time were determined to interfere the HUVEC to achieve the apoptotic model of HUVEC. The SCAD gene of HUVEC was knocked down by RNA interference sequence (siRNA274, siRNA414, siRNA679). The mRNA expression of SCAD, the protein expression of SCAD and the activity of SCAD enzyme were detected to achieve the best RNA interference sequence. The HUVEC was intervened by the best RNA interference sequence and tBHP. The cell activity and apoptosis rate, the enzyme activity of SCAD, the mRNA and protein expression of SCAD, the contents of reactive oxygen species (ROS), aderosine triphosphate (ATP) and free fatty acid (FFA) were detected to observe the effect of SCAD on apoptosis of HUVEC.
    RESULTS: (1) The cell viability, the mRNA expression and the protein expression of SCAD were decreased gradually in a concentration and time dependent manner with the increase of tBHP concentration and the prolongation of intervention time. The decline was most significant in the group of the 50 μmol/L tBHP to interfere HUVEC for 12 hours. (2) The siRNA679 transfection was the most significant in reducing SCAD mRNA and protein expressions among the three interference sequences (siRNA274, siRNA414, siRNA679). (3) Compare with blank control group, the cell viability was significantly decreased in the siRNA679 group (A value: 0.48±0.09 vs. 1.00±0.09, P < 0.01), the apoptotic rate of HUVEC was significantly increased [(29.96±2.09)% vs. (2.90±1.90)%, P < 0.01], the expression of SCAD mRNA and SCAD protein, the activity of SCAD enzyme and the content of ATP were significantly decreased [SCAD mRNA (2-ΔΔCt): 0.50±0.16 vs. 1.34±0.12, SCAD/α-Tubulin: 0.67±0.11 vs. 1.00±0.06, the activity of SCAD enzyme (kU/g): 0.38±0.04 vs. 0.53±0.04, the content of ATP (μmol/g): 0.14±0.02 vs. 0.19±0.01, all P < 0.05], the contents of FFA and ROS were significantly increased [FFA (nmol/g): 0.84±0.07 vs. 0.47±0.04, ROS (average fluorescence intensity): 647.5±23.7 vs. 434.2±46.5, both P < 0.01]. Meanwhile, SCAD siRNA treatment triggered the same apoptosis as HUVEC treated with tBHP.
    CONCLUSIONS: Down-regulation of SCAD may play an important role in HUVEC apoptosis. Increase in the expression of SCAD may become an important part in intervening HUVEC apoptosis.
    DOI:  https://doi.org/10.3760/cma.j.issn.2095-4352.2019.06.019
  34. Avicenna J Phytomed. 2019 Jul-Aug;9(4):9(4): 374-385
    Administration of troxerutin improves testicular function and structure in type-1 diabetic adult rats by reduction of apoptosis.
    Afsaneh Qadiri, Fariba Mirzaei Bavil, GholamReza Hamidian, Zohreh Zavvari Oskuye, Mahdi Ahmadi, Hajar Oghbaei, Keivan Mehri, Amir Mansour Vatankhah, Rana Keyhanmanesh.
      Objective: The glucose-reducing effects of troxerutin was previously proven. This study was conducted to evaluate troxerutin effect on testicular structure and spermatozoid parameters in type-1 diabetic adult male rats.Materials and Methods: Fifty male Wistar rats were randomly classified into 5 groups as follows: control (C), troxerutin (T), diabetic (DM), troxerutin-treated DM (DT) and insulin-treated DM (DI). Testicular structure, apoptosis, lipid peroxidation and antioxidant activity, and spermatozoid parameters were assessed 4 weeks after initiation of the interventions.
    Results: The results revealed that diabetes caused testicular stereological changes and significantly increased blood glucose level, testicular MDA content and apoptosis but decreased insulin level, testicular GPX activity, and sperm parameters compared to controls (p<0.001 to p<0.05). Administration of troxerutin and insulin could significantly reduce blood glucose level and improve testicular MDA content, testicular stereological findings and apoptosis compared to DM group (p<0.001 to p<0.05).
    Conclusion: Taken together, troxerutin, comparable to insulin, effectively improved DM-induced testicular dysfunction and sperm parameters in diabetic rats and these effects might be mediated through troxerutin's anti-apoptotic effects.
    Keywords:  Apoposis; Diabetes; Rat; Stress oxidative; Testis; Troxerutin
  35. Fish Shellfish Immunol. 2019 Jul 13. pii: S1050-4648(19)30731-4. [Epub ahead of print]
    Chlorpyrifos induced oxidative stress to promote apoptosis and autophagy through the regulation of miR-19a-AMPK axis in common carp.
    Qiaojian Zhang, Shufang Zheng, Shengchen Wang, Wei Wang, Houjuan Xing, Shiwen Xu.
      Chlorpyrifos (CPF) has become a mainly pollution in water environment. Micro-RNAs (miRNAs) play an important part in the development of apoptosis and autophagy. However, the potential mechanism of CPF induced kidney toxicity and the roles of miRNAs are still unclear. To explore the underlying mechanism, the kidney of common carp exposed to different concentrations of CPF for 40 days was used as a research object. We found that CPF could damage the ultrastructure and function of kidney; and also caused antioxidant system disorder. CPF inhibited the mRNA level of miR-19a which improved AMP-activated protein kinase (AMPK). Furthermore, the detection of apoptosis and autophagy relative genes showed that the expressions of TSC complex subunit 2 (TSC2), light chain 3 (LC3), Dynein, tumor protein 53 (p53), Bcl-2 associated X protein (Bax), caspase-3 and caspase-9 were enhanced and the expressions of nechanistic target of rapamycin (mTOR), Ras homolog mTORC1 binding (Rheb) and B-cell lymphoma (Bcl-2) were reduced in dose-dependent way. Taken together, we conclude that CPF causes oxidative stress and miR-19a-AMPK axis disorder, thereby promotes apoptosis and autophagy in common carp kidney. Our study will provide theoretical basis for toxicology research and environmental protection of CPF.
    Keywords:  Apoptosis; Autophagy; Chlorpyrifos; Common carp; MicroRNA-19a-AMPK; Oxidative stress
    DOI:  https://doi.org/10.1016/j.fsi.2019.07.022
  36. Phytomedicine. 2019 Jun 30. pii: S0944-7113(19)30171-0. [Epub ahead of print]63 153005
    Tris(8-Hydroxyquinoline)iron induces apoptotic cell death via oxidative stress and by activating death receptor signaling pathway in human head and neck carcinoma cells.
    Leong-Perng Chan, Ya-Ping Tseng, Hsiou-Yu Ding, Sheng-Ming Pan, Feng-Yu Chiang, Ling-Feng Wang, Tzung-Han Chou, Pei-Jung Lien, Cheng Liu, Po-Lin Kuo, Chia-Hua Liang.
      BACKGROUND: 8-Hydroxyquinoline derivatives have highly sensitive fluorescent chemosensors for metal ions, which are associated with anti-oxidant, anti-tumor and anti-HIV-1 properties. Head and neck squamous cell carcinoma (HNSCC) is associated with a high rate of mortality and novel anti-HNSCC drugs must be developed. Therefore, effective chemotherapy agents are required to address this public health issue.HYPOTHESIS/PURPOSE: The aim of this study was to investigate the inhibitory effect of tris(8-hydroxyquinoline)iron (Feq3) on the HNSCC and the underlying mechanism.
    STUDY DESIGN/METHODS: A novel 8-hydroxyquinoline derivative, Feq3, was synthesized. The cell viabilities were analyzed using MTT reagent. Apoptosis and the cell cycle distributions were determined by flow cytometer. Reverse transcription-polymerase chain reaction (RT-PCR), immunofluorescence, western blot, MitoSOX and CellROX stain assay were used to study the mechanism of Feq3. Feq3 combined with antioxidants NAC (N-acetylcysteine) and BSO (buthionine sulfoximine) measured the cell viability and intracellular ROS.
    RESULTS: Feq3 induced the death of HNSCC cells and caused them to exhibit the morphological features of apoptosis. Feq3 also induced apoptosis of SCC9 cells by cell cycle arrest during the G2/M phase and the induced arrest of SCC25 cells in the G0/G1 and G2/M phases, which was associated with decreased cyclin B1/cdc2 and cyclin D/cdk4 expressions. Feq3 increases reactive oxygen species (ROS) and reduces glutathione (GSH) levels, and responds to increased p53 and p21 expressions. Feq3 induced apoptosis by mitochondria-mediated Bax and cytochrome c up-expression and down-expression Bcl-2. Feq3 also up-regulated tBid, which interacts with the mitochondrial pathway and tumor necrosis factor-α (TNF-α)/TNF-Rs, FasL/Fas, and TNF-related apoptosis inducing ligand receptors (TRAIL-Rs)/TRAIL-dependent caspases apoptotic signaling pathway in HNSCC cells. However, Feq3 activates Fas but not FasL in SCC25 cells. Feq3 arrests the growth of HNSCC cells and is involved in the mitochondria- and death receptor (DR)-mediated caspases apoptotic pathway.
    CONCLUSION: This study is the first to suggest that apoptosis mediates the anti-HNSCC of Feq3. Feq3 has potential as a cancer therapeutic agent against HNSCC.
    Keywords:  Death receptor; Human head and neck carcinoma; Mitochondria; Oxidative stress; Tris(8-Hydroxyquinoline)iron
    DOI:  https://doi.org/10.1016/j.phymed.2019.153005
  37. J Cell Physiol. 2019 Jul 15.
    Syndecan-4 involves in the pathogenesis of rheumatoid arthritis by regulating the inflammatory response and apoptosis of fibroblast-like synoviocytes.
    Peian Cai, Zhenhui Lu, Tongmeng Jiang, Zetao Wang, Yifeng Yang, Li Zheng, Jinmin Zhao.
      Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease, and the pathogenesis of RA is still unknown. Rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs) are of significance in the pathogenesis of RA. In this study, three microarray profiles (GSE55457, GSE55584, and GSE55235) of human joint FLSs from 33 RA patients and 20 normal controls were extracted from the Gene Expression Omnibus Dataset and analyzed to investigate the underlying pathogenesis of RA. As analyzed by the differently expressed genes, gene ontology, Kyoto Encyclopedia of Genes and Genomes pathway enrichment, and protein-protein interaction network analysis, syndecan-4 (SDC4), a receptor of multiple cytokines and chemokines, which played a key role in the regulation of inflammatory response, was found to be an essential regulator in RA. To further validate these results, the levels of SDC4, reactive oxygen species (ROS), nitric oxide (NO), inflammation, and apoptosis in RA-FLSs were examined. SDC4-silenced RA-FLSs were also used. The results demonstrated that SDC4 and the level of ROS, NO, and inflammation were highly expressed while the apoptosis was decreased in RA-FLSs compared with normal FLSs. SDC4 silencing significantly suppressed the levels of ROS, NO, and inflammation; elevated the expression of nuclear factor erythroid 2-related factor 2; and promoted the apoptosis of RA-FLSs. Collectively, our results demonstrated a new mechanism of SDC4 in initiating the inflammation and inhibiting the apoptosis of RA-FLSs and that a potential target for the diagnosis and treatment of RA in the clinic might be developed.
    Keywords:  apoptosis; fibroblast-like synoviocytes; inflammation; rheumatoid arthritis; syndecan-4
    DOI:  https://doi.org/10.1002/jcp.29093
  38. Biomaterials. 2019 Jul 02. pii: S0142-9612(19)30429-6. [Epub ahead of print]218 119330
    Drug delivery micelles with efficient near-infrared photosensitizer for combined image-guided photodynamic therapy and chemotherapy of drug-resistant cancer.
    Shijie Zhen, Xiaoqing Yi, Zujin Zhao, Xiaoding Lou, Fan Xia, Ben Zhong Tang.
      The combination of photodynamic therapy (PDT) and chemotherapy (CT) offers a promising approach for the tumor eradication for overcoming multidrug resistance (MDR), which is a major obstacle to effective cancer treatment. However, for PDT, simultaneously achieving near-infrared (NIR) emission and efficient reactive oxygen species (ROS) generation with low dark toxicity is urgently needed but remains challenging. Herein, a series of novel fluorophores with strong NIR emission, hybridized local and charge transfer characteristics, good two-photon absorption, high photostability, low dark cytotoxicity and excellent ROS generation ability are developed. By encapsulating the NIR fluorophore (DEB-BDTO) as a photosensitizer along with a drug resistance inhibitor tariquidar (TQR) within a polymeric prodrug (PMP), a reduction-sensitive drug co-delivery system (DEB/TQR@PMP micelles) is constructed. The DEB/TQR@PMP micelles exhibit a prominent synergistic lethal effect of PDT and CT on SKOV-3 cells and SKOV-3/MDR cells, and can apparently enhance the inhibition of tumor growth compared with sole PDT or CT in the tumor-bearing mouse model. Both in vitro and in vivo experiments prove that the new NIR fluorophores are excellent photosensitizers and can furnish an efficient combination therapy of image-guided PDT and CT within drug delivery micelles, which is particularly useful for eradicating multidrug resistance cancer.
    Keywords:  Chemotherapy; Drug delivery; Near-infrared fluorophore; Photodynamic therapy; Photosensitizer
    DOI:  https://doi.org/10.1016/j.biomaterials.2019.119330
  39. ACS Nano. 2019 Jul 18.
    A Biomimetic Superoxide Disproportionation Catalyst for Anti-Aging Lithium-Oxygen Batteries.
    Chihyun Hwang, JongTae Yoo, Gwan Yeong Jung, Se Hun Joo, Jonghak Kim, Aming Cha, Jung-Gu Han, Nam-Soon Choi, Seok Ju Kang, Sang-Young Lee, Sang Kyu Kwak, Hyun-Kon Song.
      Reactive oxygen species or superoxide (O2-) to damage or age biological cells is generated during metabolic pathways using oxygen as an electron acceptor in biological systems. Superoxide dismutase (SOD) protects cells from the superoxide-triggered apoptosis by converting superoxide to oxygen and peroxide. Lithium-oxygen battery (LOB) cells have the same aging problems caused by superoxide-triggered side reactions. We transplanted the function of SOD of biological systems into LOB cells. Malonic acid-decorated fullerene (MA-C60) was used as a superoxide disproportionation chemo-catalyst mimicking the function of SOD. As expected, MA-C60 as the superoxide scavenger improved capacity retention along charge/discharge cycles successfully. A LOB cell that failed to provide a meaningful capacity just after several cycles at high current (0.5 mA cm-2) with 0.5 mAh cm-2 cut-off survived up to 50 cycles after MA-C60 was introduced to electrolyte. Moreover, the SOD-mimetic catalyst increased capacity: e.g., more than six-fold increase at 0.2 mA cm-2. Experimentally observed toroidal morphology of the final discharge product of oxygen reduction (Li2O2) and density functional theory calculation confirmed that the solution mechanism of Li2O2 formation, more beneficial than the surface mechanism from the capacity-gain standpoint, was preferred in the presence of MA-C60.
    DOI:  https://doi.org/10.1021/acsnano.9b03525
  40. Biochem Pharmacol. 2019 Jul 10. pii: S0006-2952(19)30263-1. [Epub ahead of print]
    Ginsenoside Rg5 induces G2/M phase arrest, apoptosis and autophagy via regulating ROS-mediated MAPK pathways against human gastric cancer.
    Yannan Liu, Daidi Fan.
      Ginsenoside Rg5, a rare saponin belonging to the family of protopanaxadiol ginsenosides, has been demonstrated to have potential anti-tumor effects in various cancers. However, the effect of Rg5 on human gastric cancer and the underlying molecular mechanisms remain to be elucidated. In this study, Rg5 could suppress cell proliferation by causing G2/M phase arrest. Treatment with Rg5 could induce apoptosis through the extrinsic death receptor and intrinsic mitochondrial pathways. Autophagy induction was demonstrated by the formation of autophagosomes and autophagy-related proteins. Rg5-induced cell death was drastically restored by the autophagy inhibitor 3-MA and apoptosis inhibitor Z-VAD-FMK. Moreover, the suppression of apoptosis weakened Rg5-induced autophagy, while the inhibition of autophagy attenuated Rg5-induced apoptosis. Further studies revealed that Rg5 induced ROS production and activated MAPK signaling pathways. The ROS scavenger NAC markedly diminished G2/M arrest, apoptosis, autophagy and activation of MAPK pathways induced by Rg5. The P38 inhibitor SB203580 or knockdown of P38 by siRNA clearly reversed Rg5-induced apoptosis and G2/M arrest. The JNK inhibitor SP600125 or knockdown of JNK by siRNA markedly attenuated Rg5-induced G2/M arrest, apoptosis and autophagy. The inhibition of ERK inhibitor U0126 or knockdown of ERK by siRNA clearly restored Rg5-induced apoptosis and autophagy. Finally, Rg5 significantly suppressed the growth of xenograft gastric tumors with fewer side effects. Overall, the evidence suggested that Rg5 is a novel and promising strategy for the treatment of gastric cancer owing to its high efficacy, multiple mechanisms and fewer side effects.
    Keywords:  Apoptosis; Autophagy; Ginsenoside Rg5; Human gastric cancer; MAPK; ROS
    DOI:  https://doi.org/10.1016/j.bcp.2019.07.008
  41. Oncol Rep. 2019 Jul 19.
    Protein kinase A activation by β‑Lapachone is associated with apoptotic cell death in NQO1‑overexpressing breast cancer cells.
    Sahib Zada, Jin Seok Hwang, Mahmoud Ahmed, Trang Huyen Lai, Trang Minh Pham, Dong-Hee Kim, Deok Ryong Kim.
      One million females are diagnosed worldwide every year with breast cancer, and the mortality rate of these patients remains high. Several treatments, including surgery, are available for breast cancer. β‑Lapachone (β‑Lap), a natural quinone compound, has been developed for cancer treatment due to its strong cytotoxic effect through its action on NAD(P)H:quinone oxidoreductase 1 (NQO1)‑dependent activity. However, the mechanism in regards to how β‑Lap induces cytotoxicity in breast cancer cells is still elusive. In the present study, we showed that β‑Lap induced apoptotic cell death via activation of protein kinase A (PKA) in NQO1‑overexpressing MDA‑MB‑231 human breast cancer cells. This PKA‑dependent cell death was observed solely in NQO1‑overexpressing 231 cells via the high production of reactive oxygen species (ROS). Cell survival of antioxidant [N‑acetylcysteine (NAC)]‑treated NQO1‑overexpressing 231 cells was significantly recovered, and NQO1‑negative 231 cells did not respond to β‑Lap. Antiapoptotic proteins such as Bcl2 and Bcl‑xL were decreased, while proapoptotic proteins, including cytochrome c, activation of caspase‑3, and cleavage of PARP were increased after β‑Lap treatment of NQO1‑overexpressing 231 cells. Furthermore, PKA activators, forskolin or dibutyryl‑cAMP, an analog of cAMP, aggravated the β‑Lap‑induced apoptotic cell death by decreasing antiapoptotic proteins and further activating proapoptotic proteins in NQO1‑positive 231 cells. Treatment with a PKA inhibiter, H89, significantly increased cell viability even in NQO1‑overexpressing cells treated with β‑Lap. These data showed that β‑Lap activated PKA via ROS accumulation, subsequently leading to apoptotic cell death in NQO1‑positive breast cancer cells.
    DOI:  https://doi.org/10.3892/or.2019.7243
  42. Artif Cells Nanomed Biotechnol. 2019 Dec;47(1): 2900-2908
    The protective effects of lycopus lucidus turcz in diabetic retinopathy and its possible mechanisms.
    Jinlu Liu, Sai Bhuvanagiri, Xiaohan Qu.
      The aim of the present study was to investigate the effect of Lycopus lucidus Turcz (LT) on diabetic retinopathy (DR) and its underlying mechanisms. SD rats and human retinal microvascular endothelial cells (HRECs) were applied for establishment DR model. HE and TUNEL staining were used to evaluate the pathological changes and apoptosis of retinal ganglion cells. Additionally, retinal vessels were detected by immunofluorescence staining with CD31 and VEGF. The function of BRB was observed using Evans blue. Moreover, the oxidative stress, inflammation and angiogenesis associated factors were measured respectively. The expression of p38-MAPK/NF-κB signalling proteins were detected by Western blot. The results demonstrated that pathological changes and retinal optic disc cells apoptosis in retinas of diabetic rats, both of which were reduced in the LT-treated group. And LT treatment attenuated the levels of oxidative stress, inflammation and angiogenesis factors. Importantly, the expression levels of p-p38, p-ERK, p-JNK and NF-κB were decreased. After treatment with TNF-α combined with LT, the levels of inflammatory factors were decreased but higher than the negative control. Taken together, the results suggested that LT treatment is of therapeutic benefit by ameliorating oxidative stress, inflammation and angiogenesis of DR via p38-MAPK/NF-κB signaling pathway.
    Keywords:  Diabetic retinopathy; NF-κB; angiogenesis; inflammation; p38
    DOI:  https://doi.org/10.1080/21691401.2019.1640230
  43. Cell Physiol Biochem. 2019 ;53(1): 229-241
    Extracellular Histones Induced Eryptotic Death in Human Erythrocytes.
    Ka Wing Yeung, Pui Man Lau, Hing Lun Tsang, Ho Pui Ho, Yiu Wa Kwan, Siu Kai Kong.
      BACKGROUND/AIMS: Circulating or extracellular histones (EHs) in the bloodstream act as a damage-associated-molecular-pattern (DAMP) agent that plays a critical role in the pathogenesis of many diseases such as sepsis and sterile inflammation. To date, not much information is available to describe the mechanistic relationship between human erythrocytes and the cytotoxicity of EHs, the protein members from a highly conserved histone family across species. The present study explored this key question with a hypothesis that EHs induce eryptosis.METHODS: Freshly isolated human red blood cells (RBCs) from healthy donors were treated with EHs or agents for positive controls in a physiological buffer for 3 or 24 h. After treatments, flow cytometry was employed to quantify surface phosphatidylserine (PS) exposure from annexin-V-RFP binding, cell shrinkage from flow cytometric forward scatter (FSC) analysis, Ca2+ rise by fluo-4, reactive oxygen species (ROS) production by H2DCFDA, and caspase-3 activation by FAM-DEVD-FMK measurement. Hemolysis and membarne permeabilization were estimated respectively from hemoglobin release into supernatant and calcein leakage from RBC ghosts.
    RESULTS: With positive controls for validation, EHs in the pathophsyiological range were found to accumulate annexin-V binding on cell surface, decrease FSC, upregulate ROS production, elevate Ca2+ influx and increase caspase-3 activity in a 3-h incubation. Of note, no RBC hemolysis and no calcein release from ghosts were obtained after EHs treatment for 24 h. Interestingly, external Ca2+ was not a prerequisite for the EHs-mediated ROS production and PS externalization. Also, the eryptotic hallmarks in the apoptotic RBCs were partially blocked by heparin and antibody (Ab) against Toll-like receptor 2 (TLR2).
    CONCLUSION: EHs act as a DAMP agent in the human RBCs that induces eryptosis. The cytotoxic effect is rapid as the hallmarks of eryptosis such as cell shrinkage, surface PS exposure, [Ca2+]i rise, ROS production and caspase-3 activation can be seen 3 h after treatment in a dose-dependent manner. The EHs' cytotoxic effects could be blocked by heparin and the Ab against TLR2.
    Keywords:  Apoptosis; Eryptosis; Erythrocytes; Extracellular histones; Phosphatidylserine
    DOI:  https://doi.org/10.33594/000000132
  44. Heart Fail Rev. 2019 Jul 15.
    Pharmacological preconditioning with phosphodiestrase inhibitor: an answer to stem cell survival against ischemic injury through JAK/STAT signaling.
    Manju Yadav, Pooja Kumari, Varsha Yadav, Sanjay Kumar.
      Stem cell transplantation in regenerative medicine has been widely used in various disorders including cardiovascular diseases (CVD) and emerging next-generation therapy. However, transplanted stem cell encountered ischemia/reperfusion (IR) injury which is a major challenge for stem cell survival. During the acute phase after myocardial infarction (MI) cytokine-rich hostile microenvironment, extensive immune cell infiltration and lack of oxygen have been a bottleneck in cell-based therapy. During prolonged ischemia, intracellular pH and ATP level decrease results in anaerobic metabolism and lactate accumulation. Consequentially, ATPase-dependent ion transport becomes dysfunctional, contributing to calcium overload and cell death by apoptosis and necrosis. Although O2 level revitalizes upon reperfusion, a surge in the generation of reactive oxygen species (ROS) occurs with neutrophil infiltration in ischemic tissues further aggravating the injury. Ischemic preconditioning (IPC) of stem cells with a repeated short cycle of IR results in the release of chemical signals such as NO, ROS, and adenosine which triggers a cascade of signaling events that activates protein kinase C (PKC), Src protein tyrosine kinases, and nuclear factor κB (NF-κB) and subsequently increased synthesis of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), Heme oxygenase-1 [HO-1], aldose reductase, Mn superoxide dismutase, and anti-apoptotic genes (Mcl-1, BCl-xL, c-FLIPL, c-FLIPS). Pharmacological preconditioning uses a phosphodiestrase inhibitor, another mode of protecting stem cell or heart per se from impending ischemic injury in two phases. During the early phase of cardioprotection (2 h), PC leads to increased expression of survival factors like BCl2/Bax ratio while late phase (24 h) showed activation of the JAK/STAT survival pathway. Phosphorylation of STAT3 at two crucial residues, Tyr-705 and Ser-727, allows its entry inside the nucleus and upregulates the expression of protein kinase G-1 (PKG1) which evokes cardioprotective signaling. To confirm, heart-specific conditional STAT3 knockout mice undergone IR surgery, abolishing late-phase cardioprotective effects.
    Keywords:  Ischemia/reperfusion; JAK-STAT; Phosphodiestrase; Preconditioning; Protein kinase G
    DOI:  https://doi.org/10.1007/s10741-019-09822-0
  45. Biol Trace Elem Res. 2019 Jul 15.
    Effect of a Prolonged Dietary Iron Intake on the Gene Expression and Activity of the Testicular Antioxidant Defense System in Rats.
    Enver Fehim Kocpinar, Nurdan Gonul Baltaci, Hamid Ceylan, Seyda Nur Kalin, Orhan Erdogan, Harun Budak.
      Despite the fact that iron represents a crucial element for the catalysis of many metabolic reactions, its accumulation in the cell leads to the production of reactive oxygen species (ROS), provoking pathological conditions such as cancer, cardiovascular diseases, diabetes, neurodegenerative diseases, and fertility. Thus, ROS are neutralized by the enzymatic antioxidant system for the purpose of protecting cells against any damage. Iron is a potential risk factor for male fertility. However, the mechanism of action of iron on the testicular antioxidant system at the gene and protein levels is not fully understood. Thus, the purpose of the current research was to ensure a better understanding of how the long-term iron treatment influences both gene expression and enzyme activities of the testicular antioxidant system in rat testis. The data of our study showed that a significant dose-dependent increase occurred in the iron level in rat testis. A reduction occurred in reduced glutathione (GSH) levels, which represent a marker of oxidative stress, along with long-term iron overload. The expression and activity of glucose 6-phosphate dehydrogenase (G6pd), glutathione reductase (Gr), glutathione peroxidase (Gpx), and glutathione S-transferases (Gst) were significantly affected by the presence of iron. The findings of the current research demonstrate that the long-term toxic dietary iron overload influences the gene expression and enzyme activity of the testicular antioxidant defense system, but the actual effect occurs at the protein level. This may modify the sperm function and dysfunction of the male reproductive system.
    Keywords:  Enzyme activity; Gene expression; Iron overload; Oxidative stress; Testis
    DOI:  https://doi.org/10.1007/s12011-019-01817-0
  46. Biomed Res Int. 2019 ;2019 4087160
    Cytotoxic and Antitumor Activity of Lactaptin in Combination with Autophagy Inducers and Inhibitors.
    Anastasia V Bagamanshina, Olga S Troitskaya, Anna A Nushtaeva, Anastasia Yu Yunusova, Marina O Starykovych, Elena V Kuligina, Yuri Ya Kit, Max Richter, Fabian Wohlfromm, Thilo Kähne, Inna N Lavrik, Vladimir A Richter, Olga A Koval.
      Autophagy is a degradative process in which cellular organelles and proteins are recycled to restore homeostasis and cellular metabolism. Autophagy can be either a prosurvival or a prodeath process and remains one of the most fundamental processes for cell vitality. Thus autophagy modulation is an important approach for reinforcement anticancer therapeutics. Earlier we have demonstrated that recombinant analog of human milk protein lactaptin (RL2) induced apoptosis of various cultured cancer cells and activated lipidation of microtubule-associated protein 1 light chain 3 (LC3). In this study we investigated whether autophagy inhibitors-chloroquine (CQ), Ku55933 (Ku), and 3-methyladenine (3MA)-or inducer-rapamycin (Rap)-can enhance cytotoxic activity of lactaptin analog in cancer cells and its anticancer activity in the mice model. Western Blot analysis revealed that RL2 induced short-term autophagy in MDA-MB-231 and MCF-7 cells at early stages of incubation and that these data were confirmed by the transmission electron microscopy of autophagosome/autophagolysosome formation. RL2 stimulates reactive oxygen species (ROS) production, autophagosomes accumulation, upregulation of ATG5 with processing of LC3I to LC3II, and downregulation of p62/sequestosome 1 (p62). We have shown that autophagy modulators, CQ, Ku, and Rap, synergistically increased cytotoxicity of RL2, and RL2 with CQ induced autophagic cell death. In addition, CQ, Ku, and Rap in combination with RL2 decreased activity of lysosomal protease Cathepsin D. More importantly, combining RL2 with CQ, we improved antitumor effect in mice. Detected synergistic cytotoxic effects of both types of autophagy regulators, inhibitors, and inducers with RL2 against cancer cells allow us to believe that these combinations can be a basis for the new anticancer approach. Finally, we suppose that CQ and Rap promoting of short-term RL2-induced autophagy interlinks with final autophagic cell death.
    DOI:  https://doi.org/10.1155/2019/4087160
  47. Cell Biochem Funct. 2019 Jul 18.
    The link between advanced glycation end products and apoptosis in delayed wound healing.
    Asma Shaikh-Kader, Nicolette Nadene Houreld, Naresh Kumar Rajendran, Heidi Abrahamse.
      Advanced glycation end products (AGEs) are naturally occurring molecules that start to accumulate from embryonic developmental stages and form as part of normal ageing. When reducing sugars interact with and modify proteins or lipids, AGE production occurs. AGE formation accelerates in chronic hyperglycemic conditions, and high AGE levels have been associated with the pathogenesis of various diseases. In addition, enhanced levels of AGEs have been linked to delayed wound healing as seen in patients with diabetes mellitus. Research has provided numerous ways in which a high AGE concentration results in impaired wound healing, including oxidative stress, structural and functional changes to proteins important in wound repair, an enhanced inflammatory response by activation of transcription factors, and possible exaggerated apoptosis of cells necessary to the wound repair process. Apoptosis is a naturally occurring cell death process that is significant for normal tissue functioning and plays an important role in wound repair by preventing a prolonged inflammatory response and excessive scar formation. Abnormal apoptosis affects wound healing, resulting in slow healing wounds. This review will summarize the role of AGEs in wound healing, focusing on the mechanisms by which AGEs lead to apoptosis in various cell types. The review provides the way forward for medical research and molecular studies as it focuses on the mechanisms by which AGEs induce apoptosis in various cell types, including fibroblasts, osteoblasts, neuronal cells, and endothelial cells. Reviewing the mechanisms of AGE-linked apoptosis is important in understanding the impact of high AGE levels in delayed wound healing in diabetic patients due to abnormal apoptosis of cells necessary to the wound healing process.
    Keywords:  RAGE; advanced glycation end products; apoptosis; oxidative stress; wound healing
    DOI:  https://doi.org/10.1002/cbf.3424
  48. Exp Mol Pathol. 2019 Jul 10. pii: S0014-4800(19)30400-9. [Epub ahead of print] 104282
    MiR-320a was highly expressed in postmenopausal osteoporosis and acts as a negative regulator in MC3T3E1 cells by reducing MAP9 and inhibiting PI3K/AKT signaling pathway.
    Yao Kong, Zhi-Kui Nie, Feng Li, Hong-Min Guo, Xing-Lin Yang, Shao-Feng Ding.
      BACKGROUND: Postmenopausal osteoporosis (PMO), as a frequent disease in postmenopausal women, is mainly caused by the lack of estrogen. MiR-320a has been found to abate osteoblast function and induce oxidative stress before osteoporosis. However, studies on the downstream target gene and related signaling pathway of miR-320a in PMO are still obscure. This study aims to deal with these problems.METHODS: The expression levels of miR-320a and microtubule-associated protein 9 (MAP9) in patients with osteoporosis were analyzed on the basis of the GEO database. The cells viability was determined by methylthiazolyl tetrazolium bromide (MTT). Flow cytometry and western blot were used to detect the cells apoptosis and the expression of apoptosis-related proteins, respectively. The cells differentiation-related proteins were detected by qRT-PCR and western blot. The interaction between miR-320a and MAP9 was predicted by biological software and verified by dual luciferase reporter assay and rescue assay. The expression levels of PI3K, p-PI3K, AKT and p-AKT in MC3T3-E1 cells were assessed by western blot.
    RESULTS: We observed that miR-320a was over-expressed in PMO patients and exhibited inhibitory effects on MC3T3-E1 cells activity and differentiation, as well as promoting effects on MC3T3-E1 cells apoptosis. MAP9 was verified as a target gene of miR-320a and was negatively regulated by miR-320a. Based on the GEO database, MAP9 was found to be lower expressed in PMO patients. Rescue assay demonstrated that down-regulation of MAP9 could alleviate the promoting effects of miR-320a inhibitor on MC3T3-E1 cells activity and differentiation and the inhibitory effects of miR-320a inhibitor on MC3T3-E1 cells apoptosis. Mechanically, miR-320a/MAP9 possibly took part in MC3T3-E1 cells viability, differentiation and apoptosis via mediating PI3K/AKT signaling pathway.
    CONCLUSIONS: Our outcomes demonstrated that miR-320a promoted MC3T3-E1 cells apoptosis, suppressed MC3T3-E1 cells viability and differentiation through targeting MAP9 and modulating PI3K/AKT signaling pathway, which provided theoretical support for miR-320a/MAP9 as promising targets for the treatment and prevention of PMO.
    Keywords:  MAP9; MC3T3-E1 cells; Postmenopausal osteoporosis; miR-320a
    DOI:  https://doi.org/10.1016/j.yexmp.2019.104282
  49. Am J Transl Res. 2019 ;11(6): 3481-3489
    Palbociclib improves cardiac dysfunction in diabetic cardiomyopathy by regulating Rb phosphorylation.
    Zhenggui Wang, Jing Li, Yonggang Wang, Quan Liu.
      Diabetic cardiomyopathy (DCM) is a condition associated with significant structural changes including cardiac tissue necrosis, localized fibrosis, and hypertrophy of cardiomyocytes. This study sought to assess whether and how CDK4/6 inhibitor, Palbociclib, can attenuate DCM using a streptozotocin (STZ)-induced DCM model system. In this study, we found CDK4 and CDK6 expression are significantly increased the cardiac tissue of these mice. Palbociclib treatment after initial STZ administration attenuated oxidative stress and inflammation, thereby reducing cardiomyocyte death and preserving cardiac function in these animals. In addition, Rb phosphorylation induction was found in STZ-treated mice, which was inhibited by Palbociclib treatment. In summary, Palbociclib protects mice from damage associated with DCM pathway activation, making Palbociclib is a relevant therapeutic target in the context of DCM.
    Keywords:  CDK4/6 inhibitor; DCM; apoptosis; inflammation; oxidative stress
  50. Am J Physiol Lung Cell Mol Physiol. 2019 Jul 17.
    The role of DJ-1 in human primary alveolar type II cell injury induced by e-cigarette aerosol.
    Karim Bahmed, Chih-Ru Lin, Hannah Simborio, Loukmane Karim, Mark Aksoy, Steven Kelsen, Dhanendra Tomar, Madesh Muniswamy, John W Elrod, Elise Messier, Robert J Mason, Ellen M Unterwald, Toby K Eisenstein, Gerard J Criner, Beata Kosmider.
      The alveolus participates in gas exchange, which can be impaired by environmental factors and toxins. There is an increase in using electronic cigarettes (e-cigarettes); however, their effect on human primary alveolar epithelial cells is unknown. Human lungs were obtained from non-smoker organ donors to isolate alveolar type II (ATII) cells. ATII cells produce and secrete pulmonary surfactant, restore the epithelium after damage and their metabolism highly depends on mitochondrial function. Our data indicates that human ATII cell exposure to e-cigarette aerosol increased IL-8 levels and induced DNA damage and apoptosis. We also studied the cytoprotective effect of DJ-1 against ATII cell injury. DJ-1 knockdown in human primary ATII cells sensitized cells to mitochondrial dysfunction as detected by high mitochondrial superoxide production, decreased mitochondrial membrane potential and calcium elevation. DJ-1 KO mice were more susceptible to ATII cell apoptosis and lung injury induced by e-cigarette aerosol compared to wild-type mice. Regulation of the oxidative phosphorylation (OXPHOS) is important for mitochondrial function and protection against oxidative stress. Major subunits of the OXPHOS system are encoded by both nuclear and mitochondrial DNA. We found dysregulation of OXPHOS complexes in DJ-1 KO mice after exposure to e-cigarette aerosol, which could disrupt the nuclear/mitochondrial stoichiometry, resulting in mitochondrial dysfunction. Together, our results indicate that DJ-1 deficiency sensitizes ATII cells to damage induced by e-cigarette aerosol leading to lung injury.
    Keywords:  DJ-1; alveolar type II cells; e-cigarette aerosol; lung; mitochondria
    DOI:  https://doi.org/10.1152/ajplung.00567.2018
  51. Biomed Res Int. 2019 ;2019 6740616
    Elafibranor Inhibits Chronic Kidney Disease Progression in NASH Mice.
    Hung-Cheng Tsai, Fu-Pang Chang, Tzu-Hao Li, Chih-Wei Liu, Chia-Chang Huang, Shiang-Fen Huang, Ying-Ying Yang, Kuei-Chuan Lee, Yun-Cheng Hsieh, Ying-Wen Wang, Tzung-Yan Lee, Yi-Hsiang Huang, Ming-Chih Hou, Han-Chieh Lin.
      Identification of new pharmacological approaches to inhibit the excessive fat intake-induced steatohepatitis and chronic kidney disease (CKD) is important. High-fat diet (HFD)-induced steatohepatitis and CKD share common pathogenesis involving peroxisome proliferator-activated receptor (PPAR)-α and -δ. Elafibranor, a dual PPARα/δ agonist, can ameliorate the HFD-induced steatohepatitis. Nonetheless, the effects of HFD-induced CKD had not yet explored. This study investigated the effects of elafibranor (elaf) on the progression of HFD-induced CKD in mice. In vivo and in vitro renal effects were evaluated in HFD-elaf mice receiving 12 weeks of elafibranor (from 13th to 24th week of HFD feeding) treatment. In elafibranor-treated HFD mice, increased insulin sensitivity, reduced obesity and body fat mass, decreased severity of steatohepatitis, increased renal expression of PPARα, PPARδ, SIRT1, and autophagy (Beclin-1 and LC3-II) as well as glomerular/renal tubular barrier markers [synaptopodin (podocyte marker), zona occludin-1, and cubulin], reduced renal oxidative stress and caspase-3, and less urinary 8-isoprostanes excretion were observed. Aforementioned benefits of elafibranor were associated with low renal tubular injury and tubulointerstitial fibrosis scores, less albuminuria, low urinary albumin-to-creatinine ratio, and preserved glomerular filtration rate. Acute incubation of podocytes and HK-2 cells with elafibranor or recombinant SIRT1 reversed the HFD-sera-induced oxidative stress, autophagy dysfunction, cell apoptosis, barrier marker loss, albumin endocytosis, and reuptake reduction. Besides hepatoprotective and metabolic beneficial effects, current study showed that elafibranor inhibited the progression of HFD-induced CKD through activation of renal PPARα, PPARδ, SIRT1, autophagy, reduction of oxidative stress, and apoptosis in mice with steatohepatitis.
    DOI:  https://doi.org/10.1155/2019/6740616
  52. Carbohydr Polym. 2019 Oct 15. pii: S0144-8617(19)30676-9. [Epub ahead of print]222 115009
    Preparation, structural characterization and bioactivity of 4-O-Methylglucuronoxylan from Artemisia sphaerocephala Krasch.
    Yangni Deng, Qian Liu, Tiantian Dang, Guiping Gong, Xiaoyi Chen, Rui Tang, Jing Sun, Shuang Song, Linjuan Huang, Zhongfu Wang.
      We obtained four soluble acid xylan fractions AGP-III-A, AGP-III-B, AGP-III-C and AGP-III-D from the insoluble Artemisia sphaerocephala Krasch gum (ASKG) polysaccharide by weak alkali treatment combined with H2O2-Vc oxidative degradation. Activity studies showed that the degradation components could reduce the cell viability of several cancer cell lines in a concentration-dependent manner, especially 4-O-Methylglucuronoxylan AGP-III-C with specific molecular weight and branching degree significantly reduced cancer cells viability and induced HepG2 apoptosis, also caused mitochondrial membrane dysfunction upregulated ROS levels, and induced G0/G1 arrest in HepG2 cells by cell cycle assay. Further, AGP-III-C mediates apoptosis in HepG2 cells by upregulating MAPK phosphorylation. The structure of AGP-III-C was characterized by uronic acid reduction, permethylation with GC-MS, and 2D-NMR analysis. The structure of AGP-III-C had a linear (1→4)-linked β-Xylf residue backbone with one branched 4-O-Me-α-GlcAp attached to the main chain by a (1→2)-glycosidic bond at every two β-(1→4)-Xylf units.
    Keywords:  Anticancer activity; Artemisia sphaerocephala Krasch gum; Degradation; Polysaccharide; Structure characterization
    DOI:  https://doi.org/10.1016/j.carbpol.2019.115009
  53. J Alzheimers Dis. 2019 Jul 08.
    Endothelial Mitochondrial Dysfunction in Cerebral Amyloid Angiopathy and Alzheimer's Disease.
    Rebecca Parodi-Rullán, Je Yeong Sone, Silvia Fossati.
      Alzheimer's disease (AD) is the most prevalent form of dementia. Cerebrovascular dysfunction is one of the earliest events in the pathogenesis of AD, as well as in vascular and mixed dementias. Cerebral amyloid angiopathy (CAA), the deposition of amyloid around cerebral vessels, is observed in up to 90% of AD patients and in approximately 50% of elderly individuals over 80 years of age. CAA is a strong contributor to vascular dysfunction in AD. CAA-laden brain vessels are characterized by dysfunctional hemodynamics and leaky blood-brain barrier (BBB), contributing to clearance failure and further accumulation of amyloid-β (Aβ) in the cerebrovasculature and brain parenchyma. Mitochondrial dysfunction is increasingly recognized as an important early initiator of the pathogenesis of AD and CAA. The objective of this review is to discuss the effects of Aβ on cerebral microvascular cell function, focusing on its impact on endothelial mitochondria. After introducing CAA and its etiology and genetic risk factors, we describe the pathological relationship between cerebrovascular amyloidosis and brain microvascular endothelial cell dysfunction, critically analyzing its roles in disease progression, hypoperfusion, and BBB integrity. Then, we focus on discussing the effect of Aβ challenge on endothelial mitochondrial dysfunction pathways, and their contribution to the progression of neurovascular dysfunction in AD and dementia. Finally, we report potential pharmacological and non-pharmacological mitochondria-targeted therapeutic strategies which may help prevent or delay cerebrovascular failure.
    Keywords:  Alzheimer’s disease; amyloid; apoptosis; blood-brain barrier; cerebral amyloid angiopathy; endothelial cells; mitochondria; neurodegeneration; reactive nitrogen species; reactive oxygen species
    DOI:  https://doi.org/10.3233/JAD-190357
  54. Biol Reprod. 2019 Jul 19. pii: ioz127. [Epub ahead of print]
    HNF1β protects endometriotic cells against apoptotic cell death by upregulating the expression of anti-apoptotic genes.
    Umma Hafsa Preya, Jeong-Hwa Woo, Youn Seok Choi, Jung-Hye Choi.
      The overexpression of hepatocyte nuclear factor 1 beta (HNF1β) in endometriotic lesion has been demonstrated. However, the role of HNF1β in endometriosis remains largely unknown. Human endometriotic 12Z cells showed higher level of HNF1β when compared with normal endometrial HES cells. In human endometriotic 12Z cells, HNF1β knockdown increased susceptibility to apoptotic cell death by oxidative stress, while HNF1β overexpression suppressed apoptosis. In addition, HNF1β knockdown and overexpression significantly decreased and increased, respectively, the expression of NFκB-dependent anti-apoptotic genes. Knockdown of the anti-apoptotic genes significantly reduced the HNF1β-induced resistance against oxidative stress in 12Z cells. Furthermore, HNF1β regulated the transcriptional activity of NFκB, and a NFκB inhibitor suppressed the HNF1β-enhanced NFκB-dependent anti-apoptotic gene expression and the resistance of the 12Z cells against cell death. Taken together, these data suggest that HNF1β overexpression may protect endometriotic cells against oxidative damage by augmenting anti-apoptotic gene expression.
    Keywords:  HNF1β/endometriosis; NFκB; anti-apoptosis gene; apoptosis; oxidative stress
    DOI:  https://doi.org/10.1093/biolre/ioz127
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